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MX2012003778A - Novel compounds. - Google Patents

Novel compounds.

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Publication number
MX2012003778A
MX2012003778A MX2012003778A MX2012003778A MX2012003778A MX 2012003778 A MX2012003778 A MX 2012003778A MX 2012003778 A MX2012003778 A MX 2012003778A MX 2012003778 A MX2012003778 A MX 2012003778A MX 2012003778 A MX2012003778 A MX 2012003778A
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MX
Mexico
Prior art keywords
mmol
methyl
ring
nitrogen
optionally substituted
Prior art date
Application number
MX2012003778A
Other languages
Spanish (es)
Inventor
Daniele Andreotti
Paul Bamborough
Andrew John Eatherton
Paula Louise Nichols
Karamjit Singh Jandu
Oliver James Philps
Original Assignee
Glaxo Group Ltd
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Filing date
Publication date
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of MX2012003778A publication Critical patent/MX2012003778A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Pharmacology & Pharmacy (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention discloses novel compounds inhibiting LRRK2 kinase activity, the preparation processes thereof, the compositions containing them, as well as the use in treating diseases characterized by LRRK2 kinase activity, particularly Parkinson's disease and Alzheimer's disease.

Description

NOVEL COMPOUNDS FIELD OF THE INVENTION The present invention relates to novel compounds that inhibit the activity of LRRK2 kinase, processes for its preparation, to compositions containing them and to its use in the treatment of diseases characterized by activity of LRRK2 kinase, particularly Parkinson's disease and Alzheimer's disease.
BACKGROUND OF THE INVENTION Parkinson's disease is a neurodegenerative disorder characterized by selective degeneration and cell death of dopaminergic neurons in the region of the substantia nigra of the brainstem. Parkinson's disease is generally considered to be sporadic and of unknown etiology. In the past five years, however, a large number of mutations in the leucine-rich repeat kinase 2 gene (LRRK2) has been linked to Parkinson's disease (WO2006068492 and WO2006045392). The G2019S mutation co-secretes with autosomal dominant parkinsonism and represents approximately 6% of the cases of familial Parkinson's disease and 3% of the cases of sporadic Parkinson's disease in Europe (Gilks et al., 2005, Lancet, 365: 415- 416; Jaleel et al, 2007, Biochem J, 405: 307-317). LRRK2 is a member of the ROCO protein family and all members of this family share five conserved domains. The G2019S mutation occurs in the highly conserved kinase domain and therefore it has been postulated that the G2019S mutation may have an effect on the activity of the kinase (WO2006068492). Since then it has been verified that this mutation increases the Vmax of LRRK2 for non-natural substrates, in vitro, moesin and the LRRKtide peptide (Jaleel et al., 2007, Biochem J, 405: 307-317). The amino acid substitutions in the second residue R1441 are also associated as Parkinson's disease (reviewed in Paisan-Ruiz 2009, Hum. Mutat 30: 1153-1 160) and have also been shown to elevate the activity of LRRK2 kinase by decreasing the rate of hydrolysis of GTP by the GTPase domain of LRRK2 (Guo et al., 2007 Exp Cell Res. 33: 3658-3670; West et al., 2007 Hum. Mol Gen. 6: 223-232). Overexpression of the mutant protein LRRK2 R1441 G is reported to cause symptoms of Parkinson's disease and Tau hyperphosphorylation in transgenic mouse models (Li, Y. et al., 2009, Nature Neuroscience 12: 826-828). This phenotype driven by LRRK2 is also characterized by decreased dopamine release, suggesting that LRRK2 inhibitors would be expected to positively regulate dopamine release. These data suggest that novel LRRK2 inhibitors of kinase catalytic activity could be useful for the treatment of Parkinson's disease, including idiopathic Parkinson's disease and familial Parkinson's disease, particularly familial Parkinson's disease in patients expressing LRRK2 kinase carrying the G2019S mutation or the R1441G mutation, In addition, LRRK2 inhibitors may have potential utility in the treatment of other conditions characterized by decreased dopamine levels such as withdrawal / recurrence symptoms associated with drug addiction (Rothman et al., 2008, Prog. Brain Res, 172: 385), and diseases of tauopathy characterized by Tau hyperphosphorylation such as Alzheimer's disease, argyrophilic grain disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy and inherited frontotemporal dementia and parkinsonism linked to chromosome 17 ( FTDP-17) (Goedert and Jakes, R (2005) Biochemistry et Biophysica Acta 1739 240-250).
Two additional mutations have been identified in LRRK2 that are clinically associated with the transition from mild cognitive impairment (MCI) to Alzheimer's disease (WO2007149798). These data provide additional evidence that inhibitors of LRRK2 kinase activity could be useful for the treatment of diseases such as Alzheimer's disease, other dementias and related neurodegenerative disorders.
In an experimental model of Parkinson's disease in marmosets, an elevation of LRRK2 mRNA is observed in a manner that correlates with the level of dyspnea induced by L-Dopa (Hurley, MJ et al., 2007 Eur. J. Neurosci. 26: 71-177). This suggests that LRRK2 inhibitors may have utility in mitigating such dyskinesias.
Evidence also emerges from the roles for LRRK2 in regulating the differentiation of neuronal progenitor in vitro (Milosevic, J. et al., 2009 Mol.Neurodegen.4: 25), suggesting that LRRK2 inhibitors may have utility in the production of neuronal progenitor cells in vitro for consequent therapeutic application in the cell-based treatment of CNS disorders.
It has been reported that individuals carrying the LRRK2 G2019S mutation display increased frequency of non-skin cancers, including kidney, breast, lung, prostate cancer as well as acute myelogenous leukemia (AML). Since it is reported that the G2019S mutation in LRRK2 increases the catalytic activity of the LRRK2 kinase domain, it is anticipated that there may be utility in small molecule inhibitors of LRRK2 for the treatment of cancers, especially those of kidney, breast, lung, prostate ( v.gr., solid tumors) and blood (eg, AML, Michael J. Fox Foundation for Parkinson's Research, LRRK2 Cohort Workshop, The Desmond Tutu Center, New York City, May 5-6, 2010).
EP15550 8 (Institute of Medicinal Molecular Design, Inc.) discloses N-arylsalicylamide derivatives and hydroxyaryl derivatives that are inhibitors of NF-kB activation and activation of AP-1, and their use in the treatment of neurodegenerative diseases such as Alzheimer's disease. Liechti et al. (Eur. J. Med. Chem., 2004, 39: 1-26) describes a series of salicylanilides and describes their inhibitory activity against tyrosine kinases. c Kerrecher et al., (Bioorg, Med Chem. Lett., 2005, 15 (8): 2103-2106) and WO2003000267 (AstraZeneca AB) describes a series of benzamides reported to act as glucokinase activators. WO2001064643 and WO2001064642 (Cor Therapeutics, Inc.) describe a series of benzamides which are claimed to act as Factor Xa inhibitors. Document J P51029464 (Microbial Chem Res Found) also describes a series of benzamides. Jensen and Ingvorsen (Acta Chemica Scandinavica, 1952, 6: 161-165) describe the production of 2-benzyloxy-4-nitrobenzoic acid amides. WO2003084949 describes a series of pyridinoylpiperidine compounds as 5-HT1 F agonists, and their use in the treatment of dementia. WO2003078409 (Ono Pharm Co. Ltd) describes a series of phenylacetic acid derivatives which are claimed to be prostaglandinase D2 DP receptor antagonists. EP796847 (Shiseido Co Ltd) describes pyridine derivatives which are claimed to be useful in the treatment of peptic ulcers. WO2006003923 and JP2007176799 (Sankyo Co Ltd) describe substituted benzene compounds as modulators of liver X-receptor for use in the treatment of numerous diseases including Alzheimer's disease. WO2007125103 (Novo Nordisk AS) describes a series of benzamide compounds as glucokinase activators. WO2005000309 (Lonix Pharm Ltd) describes a series of benzene derivatives as inhibitors of SNS sodium channels. WO2004099170 (Inst.
Pharm Discovery LLC) describes phenyl substituted carboxyl acid compounds as inhibitors of protein tyrosine phosphatase. W09948492 (Japan Tobacco Inc.) describes amide derivatives as nociceptin antagonists. WO9850030 (Univ Pittsburgh) discloses substituted benzene compounds which are useful in the treatment or prophylaxis of restenosis, intimal hyperplasia associated with restenosis, atherosclerosis and cancer. WO9900121 (Eli Lilly &Co) describes Factor Xa inhibitors.
BRIEF DESCRIPTION OF THE INVENTION present invention provides, in a first aspect, compound of the formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament where: A represents pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-5-yl, 1,3-oxazol-2-yl, 1 H-pyrazol-4-yl or isoxazol-4-yl or a group of the formula (a) wherein * represents the point of attachment: wherein when A represents pyridin-3-yl, the pyridinyl ring may be optionally substituted in the 2-position by fluoro, methoxy or CH 2 OH, in the 4-position by methyl or CH 2 OH, or in the 5-position by fluoro; when A represents IH-pyrazol-4-yl, the pyrazolyl ring may be optionally substituted at the 1-position by methyl, and where A represents isoxazol-4-yl, the isoxazolyl ring may be optionally substituted at the 3-position by methyl or in the 5 position by methyl; R1 represents halogen, C1-3 hydroxyhalogenoalkyl, CN, -0 (CH2) 20 (CH2) 2NH2, -CNOH, (0) n (CH2) pR1 °, - (CO) R10, R3, - (S02) R13, (Ci-3 alkylene) (CO) qR14, (CH = CH) (CO) R14, (C1-3 alkylene) NHCOR14, monoheterocyclic ring containing -O-nitrogen with the proviso that the atom directly attached the oxygen is not nitrogen, or a nitrogen-containing heteroaryl ring, wherein the nitrogen-containing monoheterocyclic ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing heteroaryl ring is optionally substituted by one, two or three groups selected from NH2, (Ci-3 alkylene) R13, (Ci.3 alkylene) (CO) qR14, Ci-3 alkyl and halogen; n and q independently represent 0 or 1; p represents 1, 2 0 3; R2, R3, R4, R5 and R6 independently represent hydrogen, halogen, CN, Ci-3 alkyl or Ci.3 alkoxy; R7 and R8 independently represent hydrogen or alkyl of C1-2 ', R9 represents hydrogen, halogen, C1-2 alkyl, C1.2 alkoxy, -CH2C02H or -CONHCH3; R 10 represents hydrogen, d-3 alkyl, -NR 11 R 12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups; R11 and R12 are independently selected from hydrogen and C1-3alkyl, wherein said C1.3alkyl group is optionally substituted with one, two or three halogen, hydroxy, cyano or Ci-2alkoxy groups; R 3 represents -NR 1R12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached by a nitrogen atom; Y R14 represents hydroxy or Ci-3 alkoxy; with the proviso that the compound of the formula (I) is not: 2 - [(phenylmethyl) oxy] - / V-3-pyridinyl-5- (1-pyrrolidinylsulfonyl) benzamide; or 2-. { [(3,4-difluorophenyl) methyl] oxy} -5- (1-hydroxyethyl) - / \ / - 4-pyridazinylbenzamide.
The term "halogen", as used herein, refers to a fluoro, chloro, bromo or iodo group.
The term 'Cx.y alkyl', as used herein, refers to a straight or branched saturated hydrocarbon group containing x a and carbon atoms. Examples of C1-3 alkyl groups include methyl, ethyl, n-propyl and isopropyl.
The term "halogenalkyl of Cx.y ', as used herein, refers to a group Cx.y.alkyl, as defined herein, wherein at least one hydrogen atom is replaced by halogen. Examples of such groups include fluoroethyl, trifluoromethyl ortrifluoroetyl and the like.
The term "Cx-y alkylene", as used herein, refers to a divalent linear or branched saturated hydrocarbon group containing x a and carbon atoms. Examples of alkylene groups of C3 include, CH2, CH2CH2, CH2CH2CH2, CH (CH3) CH2, CH (CH3) 2 and CH2CH (CH3).
The term 'Cx-y alkoxy', as used herein, refers to a group of the formula -O-Cx-y alkyl, wherein Cx.y-alkyl is defined as above. Examples of Ci-3 alkoxy groups include methoxy, ethoxy, n-propoxy and isopropoxy.
The term 'nitrogen-containing monoheterocyclic ring', as used herein, refers to a 4-7 membered monocyclic ring which may be saturated or partially unsaturated, and which contains at least one nitrogen atom. Optionally, the ring may contain 1 to 3 of other heteroatoms selected from oxygen, nitrogen or sulfur. Examples of nitrogen containing heterocyclyl groups include which pyrrolidinyl, azetidinyl, pyrazolidinyl, oxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, hydantoinyl, valerolactamyl, tetrahydropyridinyl, tetrahydropyrimidinyl, diazepanyl, azepanyl and the like.
The term 'heteroaryl ring containing nitrogen', as used herein, refers to an aromatic 5-6 membered monocyclic ring, said monocyclic aromatic ring contains at least one nitrogen atom and 1 to 3 additional heteroatoms selected from oxygen , nitrogen and sulfur.
Examples of such monocyclic aromatic rings include, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl, pyridyl, triazinyl, tetrazinyl and the like.
In further aspects of the invention, the invention provides a compound of the formula (I) or a salt thereof, and a pharmaceutical composition comprising the compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. .
DETAILED DESCRIPTION OF THE INVENTION As described above, in a first aspect, the invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament. where: A represents pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-5-yl, 1,3-oxazol-2-yl, 1 H- pyrazol-4-yl or isoxazol-4-yl or a group of the formula (a) wherein * represents the point of attachment: wherein when A represents pyridin-3-yl, the pyridinyl ring may be optionally substituted in the 2-position by fluoro, methoxy or CH 2 OH, in the 4-position by methyl or CH 2 OH, or in the 5-position by fluoro; when A represents-yl, 1H-pyrazol-4 the pyrazolyl ring may be optionally substituted in the 1 position by methyl, and wherein A represents isoxazole-4-yl, ring isoxazoiilo may be optionally substituted in position 3 by methyl or in the 5 position by methyl; R represents halogen, Ci-3 haloalkyl, hydroxy, CN -0 (CH2) 20 (CH2) 2NH2, -CNOH, (0) n (CH2) pR °, - (CO) R10 R13, - (S02) R13, (C1-3 alkylene) (CO) qR14, (CH = CH) (CO) R14, (Ci-3 alkylene) NHCOR14, monoheterocyclic ring containing -O-nitrogen with the proviso that the atom directly attached to oxygen is not nitrogen or a heteroaryl ring containing nitrogen, wherein the monoheterocyclic ring containing nitrogen is optionally substituted with one, two or three methyl groups and wherein the ring nitrogen containing heteroaryl is optionally substituted by one, two or three groups selected from NH2, alkylene of C -3R13, (alkylene of Ci.3) (CO) qR14, alkyl of d-3 and halogen; n and q independently represent 0 or 1; p represents 1, 2 or 3; R2, R3, R4, R5 and R6 independently represent hydrogen, halogen, CN, C- | 3 alkyl or Ci-3 alkoxy; R7 and R8 independently represent hydrogen or alkyl of C-i-2; R9 represents hydrogen, halogen, alkyl of 1-2, alkoxy of Ci-2, -CH2C02H or -CONHCH3¡ R 10 represents hydrogen, C 1-3 alkyl, -NR 11 R 12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups; R1 and R12 are independently selected from hydrogen and C1-3 alkyl, wherein said Ci-3 alkyl group is optionally substituted with one, two or three halogen, hydroxy, cyano or Ci-2 alkoxy groups; R13 represents -NR11R12, or a monoheterocyclic ring that contains nitrogen, said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached by a nitrogen atom; Y R14 represents hydroxy or C1-3 alkoxy; with the proviso that the compound of the formula (I) is not: 2 - [(phenylmethyl) oxy] - / V-3-pyridinyl-5- (1-pyrrolidinylsulfonyl) benzamide; or 2-. { [(3,4-difluorophenyl) methyl] oxy} -5- (1-hydroxyethyl) - / \ / - 4-pyridazinylbenzamide.
In one embodiment, the compound of the formula (I) is not 5-bromo-2 - [(phenylmethyl) oxy] - / V-2-pyridinylbenzamide. In another embodiment, the compound of the formula (I) is not 5-bromo-2 - [(phenylmethyl) oxy] - / 2-pyridinylbenzamide, N- [2- (hydroxymethyl) -3-pyridinyl] -2 - [(phenylmethyl) oxy] -5- (4-pyridinyl) benzamide,? / - [4- (hydroxymethyl) -3-pyridinyl] -2 - [(phenylmethyl) oxy] -5- (4-pyridinyl) benzamide, N- (5-methyl-4-isoxazolyl)) - 2 - [(phenylmethyl) oxy] -5- (4-pyridinyl) benzamide, 5- (aminomethyl) -2-. { [. { 3,4-difluorophenyl) methyl] oxy} -N-3-pyridinylbenzamide or (4 {. {[[(3,4-difluorophenyl) methyl] oxy} - 3 - [(3-pyridinylamino) carbonyl)] phenyl} methyl) methyl carbamate.
In a further aspect, the invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament wherein: A represents pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-5-yl or a group of the formula (a) wherein * represents the point of attachment: R1 represents halogen, hydroxy, CN, -R10 or -OR10; R 2, R 3, R 4, R 5 and R 6 independently represent hydrogen, halogen, CN, C 1-3 alkyl or C 1-3 alkoxy; R7 and R8 independently represent hydrogen or alkyl of Ci-2Í R9 represents hydrogen, halogen, Ci-2 alkyl, d.2 alkoxy, -CH2C02H or -CONHCH3; R 0 represents hydrogen, Ci-3 alkyl, -NR 1 R 12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups; Y R11 and R12 are independently selected from hydrogen and C1-3 alkyl, wherein said C3 alkyl group is optionally substituted with one, two or three halogen, hydroxy, cyano or Ci-2 alkoxy groups; In one embodiment, the compound of the formula (I) is not 5-bromo-2 - [(phenylmethyl) oxy] - / V-2-pyridinylbenzamide. In another embodiment, the compound of the formula (I) is not 5-bromo-2 - [(phenylmethyl) oxy] - / 2-pyridinylbenzamide or 5- (aminomethyl) -2-. { [. { 3,4-difluorophenyl) methyl] oxy} -A / -3-pyridinylbenzamide.
The compounds of formula (I) or pharmaceutically acceptable salts thereof are inhibitors of LRRK2 kinase activity and are therefore believed to be of potential use in the treatment of neurological disorders including Parkinson's disease, Alzheimer's disease, dementia ( including Lewy body dementia and vascular dementia), age-related memory dysfunction, mild cognitive impairment, argyrophilic grain disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia, and parkinsonism linked to chromosome 17 (FTDP -17), withdrawal symptoms / recurrence associated with drug addiction, dyspepsia induced by L-Dopa, and cancer of kidney, breast, lung, prostate as well as acute myelogenous leukemia (AML).
In the context of the present invention, the treatment of Parkinson's disease refers to the treatment of idiopathic Parkinson's disease and familial Parkinson's disease. In one embodiment, familial Parkinson's disease includes patients expressing LRRK2 kinase carrying the G2019S mutation or the R1441G mutation. The treatment of Parkinson's disease can be symptomatic or it can be a disease modifier. In one embodiment, the treatment of Parkinson's disease refers to symptomatic treatment.
The compounds of the present invention may also be useful for treating patients identified as being susceptible to progression to severe parkinsonism by means of one or more subtle features associated with disease progression such as family history, olfactory deficits, constipation, cognitive defects, indicators so as to walk or biological disease progression gained from molecular, biochemical, immunological or imaging technology. In this context, the treatment can be symptomatic or disease modifier.
In the context of the present invention, the treatment of Alzheimer's disease refers to the treatment of idiopathic Alzheimer's disease and familial Alzheimer's disease. The treatment of Alzheimer's disease can be symptomatic or it can be a disease modifier. In one embodiment, the treatment of Alzheimer's disease refers to symptomatic treatment. Similarly, the treatment of dementia (including Lewy body dementia and vascular dementia), age-related memory dysfunction, mild cognitive impairment, argyrophilic grain disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia inherited and parkinsonism linked to chromosome 17 (FTDP-17) and cancer of kidney, breast, lung, prostate as well as acute myelogenous leukemia (AML) can be symptomatic or can be disease modifier. In one embodiment, the treatment of dementia (including Lewy body dementia and vascular dementia), age-related memory dysfunction, mild cognitive impairment, argyrophilic grain disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia inherited and parkinsonism linked to chromosome 17 (FTDP-17), and cancer of kidney, breast, lung, prostate as well as acute myelogenous leukemia (AML) refers to symptomatic treatment.
In the context of the present invention, the treatment of withdrawal symptoms / recurrence associated with drug addiction and dyspepsia induced by L-Dopa refers to symptomatic treatment.
Accordingly, in a second aspect, the invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof wherein A, n, p, q, R, R2, R3, R4, R5, R6, R7, R8, R9, R10, R1, R12, R13 and R4 are as defined above for use in the treatment of the above disorders, and in particular Parkinson's disease and Alzheimer's disease. The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein A, n, p, q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 , R 2, R 3 and R 14 are as defined above for use in the prophylaxis of Parkinson's disease, Alzheimer's disease, dementia (including Lewy body dementia and vascular dementia), age-related memory dysfunction, cognitive impairment mild, argyrophilic grain disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and kidney, breast, lung, prostate cancer as well as acute myelogenous leukemia (AML ), particularly Parkinson's disease and Alzheimer's disease.
The invention further provides a method of treating the above disorders, particularly Parkinson's disease and Alzheimer's disease, in mammals including humans, which comprises administering to the patient a therapeutically effective amount of a compound of the invention.
Formula (I) or a pharmaceutically acceptable salt thereof wherein A, n, p, q, R, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R3 and R14 are as defined before.
The invention also provides the use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof wherein A, n, p, q, R, R2, R3, R4, R5, R6, R7, R8, R9, R10 , R11, R12, R13 and R14 are as defined above in the manufacture of a medicament for use in the treatment of the above disorders, and particularly Parkinson's disease and Alzheimer's disease. The invention also provides the use of the compound of the formula (I) or a pharmaceutically acceptable salt thereof wherein A, n, p, q, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 , R11, R2, R3 and R14 are as defined above in the manufacture of a medicament for use in the prophylaxis of Parkinson's disease, Alzheimer's disease, dementia (including Lewy body dementia and vascular dementia), dysfunction of age-related memory, mild cognitive impairment, argyrophilic grain disease, Pick disease, corticobasal degeneration, progressive supranuclear palsy, inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and kidney, breast, lung cancer, prostate as well as acute myelogenous leukemia (AML), particularly Parkinson's disease and Alzheimer's disease.
The invention also provides the use of LRRK2 inhibitors in the production of neuronal progenitor cells in vitro for consequent therapeutic application in the treatment of cells and disorders of the CNS, In a third aspect, the invention provides a compound of the formula (I) or a salt thereof where: A represents pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-5-yl, 1,3-oxazol-2-yl, 1 H-pyrazol-4-yl or isoxazol-4-yl or a group of the formula (a) wherein * represents the point of attachment: wherein when A represents pyridin-3-yl, the pyridinyl ring may be optionally substituted in the 2-position by fluoro, methoxy or CH 2 OH, in the 4-position by methyl or CH 2 OH, or in the 5-position by fluoro; when A represents 1 H-pyrazol-4-yl, the pyrazolyl ring may be optionally substituted at the 1-position by methyl, and where A represents isoxazol-4-yl, the isoxazolyl ring may be optionally substituted at the 3-position. by methyl or in the 5 position by methyl; R represents halogen, halogenalkyl of Ci-3, hydroxy, CN, -0 (CH2) 20 (CH2) 2NH2, -CNOH, (0) n (CH2) pR1 °, - (CO) R10, R13, - (S02) R13, (C1-3 alkylene) (CO) qR14, (CH = CH) (CO) R14, (C1-3 alkylene) NHCOR14, monoheterocyclic ring containing -O-nitrogen with the proviso that the atom directly attached the oxygen is not nitrogen, or a nitrogen-containing heteroaryl ring, wherein the nitrogen-containing monoheterocyclic ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing heteroaryl ring is optionally substituted by one, two or three groups selected from NH2, (C1-3 alkylene) R13, (Ci-3 alkylene) (CO) qR14, C3 alkyl and halogen; n and q independently represent 0 or 1; p represents 1, 2 or 3; R2, R3, R4, R5 and R6 independently represent hydrogen, halogen, CN, C3-alkyl or Ci-3-alkoxy; R7 and R8 independently represent hydrogen or alkyl of Ci-2¡ R9 represents hydrogen, halogen, Ci-2 alkyl, Ci alkoxy. 2, -CH2CO2H or -CONHCH3¡ R10 represents hydrogen, Ci-3 alkyl, -NR 1R12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups; R1 and R12 are independently selected from hydrogen and C1-3 alkyl, wherein said Ci-3 alkyl group is optionally substituted with one, two or three halogen, hydroxy, cyano or Ci-2R alkoxy groups represents -NR1 R12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and in where the nitrogen-containing monoheterocyclic ring is attached by a nitrogen atom; Y R14 represents hydroxy or alkoxy of ???; with the proviso that the compound of the formula (I) is not: 2 - [(phenylmethyl) oxy] - / V-3-pyridinyl-5- (1-pyrrolidinylsulfonyl) benzamide; or 2-. { [(3,4-difluorophenyl) methyl] oxy} -5- (1-hydroxyethyl) - / V-4-pyridazinylbenzamide. 5-bromo-2- (2-chlorobenzyloxy) -N- (pyridin-3-yl)) benzamide; 5-chloro-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide; 5-bromo- / V-. { 3 - [(methylamino) carbonyl] phenyl} -2- [. { phenylmethyl) oxy] benzamide or 5-chloro-2 - [(2-cyanophenyl) methoxy] -N-phenylbenzamide.
In one embodiment, the compound of the formula (I) is not 5-bromo-2- [(phenylmethyl) oxy] - / S / -2-pyridinylbenzamide. In another embodiment, the compound of the formula (I) is not 5-bromo-2- [. { phenylmethyl) oxy] - / V-2-pyridinylbenzamide,? / - [2- (hydroxymethyl) -3-pyridinyl] -2 - [(phenylmethyl) oxy] -5- (4-pyridinyl) benzamide - / \ / - [ 4- (hydroxymethyl) -3-pyridinyl] -2 - [(phenylmethyl) oxy] -5- (4-pyridinyl) benzamide, A / - (5-methyl-4-isoxazolyl)) - 2 - [(phenylmethyl) oxy] ] -5- (4-pyridinyl) benzamide, 5- (aminomethyl) -2-. { [. { 3,4-d-fluoro-phenyl) methyl] oxy} -A / -3-pyridinylbenzamide or. { . { 4-. { [(3,4-difluorophenyl) methyl] oxy} - 3- [(3-pyridinylamino) carbonyl)] phenyl} methyl) methyl carbamate.
In a further aspect, the invention provides a compound of the formula (I) or a salt thereof where: A represents pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-5-yl or a group of the formula (a) wherein * represents the point of attachment: R1 represents halogen, hydroxy, CN, -R10 or -OR10; R 2, R 3, R 4, R 5 and R 6 independently represent hydrogen, halogen, CN, C 1 -3 alkyl or C 1-3 alkoxy; R7 and R8 independently represent hydrogen or alkyl of C1-2; R9 represents hydrogen, halogen, C1.2alkyl, C1.2alkoxy, -CH2CO2H or -CONHCH3; R10 represents Ci_3 alkyl, optionally substituted with - NR 11 R 12, or a nitrogen-containing monoheterocyclic ring that is optionally substituted with one, two or three methyl groups; Y R11 and R12 are independently selected from hydrogen and C3 alkyl, wherein said C1.3 alkyl group is optionally substituted with one, two or three halogen, hydroxy, cyano or Ci-2 alkoxy groups; with the proviso that the compound of the formula (I) is not: 5-bromo-2- (2-chlorobenzyloxy) -N- (pyridin-3-yl)) benzamide; 5-chloro-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide; 5-bromo-A / -. { 3 - [(methylamino) carbonyl] phenyl} -2-[. { phenylmethyl) oxy] benzamide; or 5-chloro-2 - [(2-cyanophenyl) methoxy] -N-phenylbenzamide.
In an embodiment of this type, the compound of the formula (I) is not 5-bromo-2- [. { phenylmethyl) oxy] - / V-2-pyridinylbenzamide. In another embodiment, the compound of the formula (I) is not 5-bromo-2 - [(phenylmethyl) oxy] - / \ / - 2-pyridinium] benzamide or 5- (aminomethyl) -2-. { [(3,4-difluorophenyl) methyl] oxy} - / \ / - 3-pyridinylbenzamide.
In one embodiment of the compound of the formula (I), R1 represents.
- - (O) n (CH2) pR10; or - - (CO) R10; wherein R 0 represents hydrogen, Ci-3 alkyl, -NR 11 R 12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups, wherein n represents 0 or 1 and wherein represents 1, 2 or 3.
In a more particular embodiment, R represents - (CO) R10, wherein R10 represents hydrogen, C3 alkyl, -NR1 R12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three groups methyl. Most particularly, R 1 represents - (CO) R 10, wherein R 0 represents hydrogen, C 1-3 alkyl, -NR 1 R 12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups and said The monocyclic ring is attached to the carbonyl group by a nitrogen atom.
In an alternative embodiment, R represents - (0) n (CH2) pR1 °, wherein R 0 represents hydrogen, d-3 alkyl, -NR 11 R 12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups, wherein n represents 0 or 1 and wherein p represents 1, 2 or 3. Very particularly, R represents - (O) n (CH2) pR10, wherein R10 represents hydrogen, Ci-3 alkyl, -NR 11 R 12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups, wherein n represents 0 or 1 and wherein p represents 1.
In certain embodiments, wherein R1 represents - (0) n (CH2) pR10 or - (CO) R10, R10 represents a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups. Most particularly, R10 represents a monoheterocyclic ring containing nitrogen selected from the group consisting of piperidinyl, piperazinyl pyrrolidinyl and morpholinyl, said ring is optionally substituted with one, two or three methyl groups.
Most particularly, R 0 represents: piperidinyl (e.g., piperidin-1-yl or piperidin-4-yl)), which is optionally substituted with one, two or three methyl groups; - piperazinyl (e.g., piperazin-1-yl) which is optionally substituted with one, two or three methyl groups; pyrrolidinyl (e.g., pyrrolidin-1-yl or pyrrolidin-2-yl)) which is optionally substituted with one, two or three methyl groups; or morpholinyl (e.g., morpholin-4-yl).
Very particularly, R10 represents: unsubstituted piperidin-1-yl); piperidin-4-yl optionally substituted with one, two or three methyl groups (e.g., 1-methylpiperidin-4-yl); piperazin-1-yl optionally substituted with one, two or three methyl groups (e.g., 4-methylpiperazin-1-yl); unsubstituted pyrrolidin-1-yl); pyrrolidin-2-yl optionally substituted with one, two or three methyl groups (e.g., 1-methyl pyrrolidin-2-yl); or unsubstituted morpholin-4-yl.
In embodiments in which R represents - (CO) R10, R10 represents: unsubstituted piperidin-1-yl); piperidin-4-yl optionally substituted with one, two or three methyl groups (e.g., 1-methylpiperidin-4-yl); piperazin-1-yl optionally substituted with one, two or three methyl groups (e.g., 4-methylpiperazin-1-yl); unsubstituted pyrrolidin-1-yl); or - unsubstituted morpholin-4-yl.
In other embodiments in which R1 represents - (0) n (CH2) pR10 or - (CO) R10, R10 represents -NR11R12, wherein R11 and R12 are independently selected from hydrogen and Ci-3 alkyl, wherein the group 0 ^ 3 alkyl is optionally substituted with one, two or three halogen, hydroxy, cyano or Ci-2 alkoxy groups. Most particularly, R 11 and R 12 are independently selected from hydrogen and d-3 alkyl. Most particularly, R 11 and R 12 are independently selected from hydrogen and methyl.
In a further embodiment, R1 represents R13 or - (S02) 3 wherein R13 represents -NR11R12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and wherein the monoheterocyclic ring containing nitrogen is bound to the sulfur by a nitrogen atom, In a more particular embodiment, R1 represents R13, where R13 represents -NRR12 or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached by a nitrogen atom.
In an alternative embodiment, R1 represents - (S02) R13, in where R 13 represents -NR 1 R 12 or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached to the sulfur by a nitrogen atom.
In certain embodiments where R1 represents R13 or - (SO2) R13, R13 represents a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached by a nitrogen atom. Most particularly, R13 represents a monoheterocyclic ring containing nitrogen selected from the group consisting of piperidinyl, piperazinyl pyrrolidinyl and morpholinyl, said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached by a nitrogen atom.
Most particularly still, R13 represents: - piperidinyl (e.g., piperidin-1-yl or piperidin-4-yl)) which is optionally substituted with one, two or three methyl groups; piperazinyl (e.g., piperazin-1-yl) which is optionally substituted with one, two or three methyl groups; pyrrolidinyl (e.g., pyrrolidin-1-yl) which is optionally substituted with one, two or three methyl groups; or morpholinyl (e.g., morpholin-4-yl).
Very particularly still, R 3 represents: unsubstituted piperidin-1-yl); piperidin-4-yl optionally substituted with one, two or three methyl groups (e.g., 1-methylpiperidin-4-yl); piperazin-1-yl optionally substituted with one, two or three methyl groups (e.g., 4-methylpiperazin-1-yl) unsubstituted pyrrolidin-1-yl); or unsubstituted morpholin-4-yl.
In other embodiments in which R1 represents R13 or - (S02) R13, R13 represents -NR1 R12, wherein R11 and R12 are independently selected from hydrogen and alkyl, wherein said Ci-3 alkyl group is optionally substituted with one, two or three halogen, hydroxy, cyano or C2-alkoxy groups Very particularly, R11 and R12 are independently selected from hydrogen and Ci-3 alkyl. Most particularly still, R11 and R12 are independently selected from hydrogen and methyl.
In an alternative embodiment, R1 represents: (Ci-3 alkylene) (CO) qR 4 (CH = CH) (CO) R14; or (C1-3 alkylene) NHCOR14; wherein R14 represents hydroxyl or C-i-3 alkoxy and q represents 0 or 1.
In a further embodiment, R1 represents a nitrogen-containing heteroaryl ring, said nitrogen-containing heteroaryl ring is optionally substituted by one, two or three groups selected from NH2, Ci-3 alkylene, (Ci-3 alkylene) ( CO) qR14, Ci-3 alkyl and halogen. Most particularly, R represents a nitrogen-containing heteroaryl ring, said nitrogen-containing heteroaryl ring is optionally substituted by a group selected from NH2, (Ci.3 alkylene) R13, (Ci-3 alkylene) (CO) qR14 , C1-3 alkyl and halogen.
Most particularly, R1 represents pyridinyl or pyrazolyl, said pyridinyl or pyrazolyl group is optionally substituted by one, two or three groups selected from NH2, (Ci.3 alkylene) 3, (alkylene of ?? - 3) (CO) qR14, Ci_3 alkyl and halogen. Most particularly still, R1 represents pyridinyl or pyrazolyl, said pyridinyl or pyrazolyl group is optionally substituted by a group selected from NH2, alkylene of Ci-3R13, (alkylene of Ci-3) (CO) qR14, alkyl of C1.3 and halogen .
Very particularly still, R1 represents: pyridin-4-yl optionally substituted by an NH2 or halogen group (e.g., 2-aminopyridin-4-yl, 2-fluoropyridin-4-yl); - unsubstituted pyridin-3-yl); 1 H-pyrazol-4-yl optionally substituted by a group selected from 2- (4-morpholinyl)) ethyl, 2- (methyloxy) ethyl or methyl (e.g., 1- [2- (4-morpholinyl)) ethyl] -1 H -pyrazol-4-yl, 1- [2- (methyloxy) ethyl] -1 H -pyrazol-4-yl, 1-methyl-1 H -pyrazol-4-yl); or - H-pyrazol-5-yl optionally substituted by a methyl group (e.g., 1 methyM H-pyrazol-5-yl).
In another embodiment, R1 represents monoheterocyclic ring containing -O-nitrogen, said ring is optionally substituted with one, two or three methyl groups with the proviso that the atom directly attached to oxygen is not nitrogen. In a more particular embodiment, R represents piperidinyloxy wherein the piperidine ring is optionally substituted with one, two or three methyl groups. Most particularly, R 1 represents piperidinyloxy, wherein the piperidine ring is optionally substituted with a methyl group (e.g., 1-methylpiperidin-4-yloxy).
In one embodiment of the compound of the formula (I), R1 represents: halogen (e.g., bromine, chlorine, fluoro); C1-3 halogenoalkyl (e.g., trifluoromethyl); hydroxy; CN; -0 (CH2) 20 (CH2) 2NH2; or -CNOH In a more particular embodiment, R represents CN.
In a further embodiment, R1 represents halogen, very particularly bromine.
In another embodiment, R1 represents halogenoalkyl of Ci-3 (e.g., trifluoromethyl).
In certain embodiments of the compound of the formula (I), R 1 represents bromine, chlorine, fluoro, CN, methyl, isopropyl, hydroxy, methoxy, ethoxy, piperidinyl, piperazinyl or piperidinyloxy, wherein said methoxy and ethoxy group are optionally substituted with a dimethylamino group and wherein said piperidinyl, piperazinyl or piperidinyloxy groups are optionally substituted with one, two or three methyl groups.
In an alternative embodiment, R1 represents C1.3O alkyl, very particularly isopropyl and methyl. In one embodiment, R represents sopropyl.
In one embodiment, R represents C 1 -3 alkoxy optionally substituted with a group -NR 1 R 12, wherein R 1 and R 12 are independently selected from hydrogen and Ci-3 alkyl. In a more particular embodiment, R 1 represents C 1-3 alkoxy optionally substituted with a group -NR 1 R 12 wherein R 1 and R 12 each represent C 1-3 alkyl (e.g., methyl). Most particularly still, R represents methoxy or 2- (dimethylamino) ethoxy.
In another embodiment, R represents a nitrogen-containing monoheterocyclic ring (e.g., piperidinyl, piperazinyl) optionally substituted with one, two or three methyl groups. In a more particular embodiment R1 represents a nitrogen-containing monoheterocyclic ring (e.g., piperidinyl, piperazinyl) optionally substituted with a methyl group. Most particularly still, R represents unsubstituted piperidin-1-yl, or piperazin-1-yl optionally substituted with a methyl group.
In a further embodiment, R1 represents a nitrogen-containing monoheterocyclyloxy group (e.g., piperidinyloxy) optionally substituted with one, two or three methyl groups. Most particularly, R1 represents a monoheterocyclyloxy group containing nitrogen (e.g. piperidinyloxy) optionally substituted with a methyl group. Most particularly still, R 1 represents piperidin-4-yl) oxy optionally substituted with a methyl group.
In another embodiment, R2, R3, R4, R5 and R6 independently represent hydrogen, halogen, CN, and C1.3 alkoxy. Most particularly, R2, R3, R4, R5 and R6 independently represent: hydrogen; halogen (e.g., fluoro or chloro); CN; or - Ci-3 alkoxy (e.g., methoxy).
Most particularly, R2, R3, R4, R5 and R6 independently represent hydrogen or fluoro. In one embodiment, one or two of R2, R3, R4, R5 and R6 represent fluoro and the remaining groups represent hydrogen.
In one embodiment, R2, R3, R4, R5 and R6 each represent hydrogen. In an alternative embodiment, one of R2, R3, R4, R5 and R6 represents halogen, CN, C1-3 alkyl or C1-3 alkoxy and the remaining groups are each hydrogen.
In one embodiment, R3, R4, R5 and R6 each represent hydrogen and R2 represents: halogen (e.g., fluoro or chloro); CN; or C1-3 alkoxy (e.g., methoxy).
In a more particular embodiment, R3, R4, R5 and R6 each represents hydrogen and R2 represents chlorine.
In an alternative embodiment, R3, R4, R5 and R6 each represent hydrogen and R2 represents fluoro.
In a further embodiment, R2, R4, R5 and R6 each represent hydrogen and R3 represents: halogen (e.g., fluoro, chloro); CN; or Ci_3 alkoxy (e.g., methoxy).
In a more particular embodiment, R2, R4, R5 and R6 each represent hydrogen and R3 represents chloro or CN.
In an alternative embodiment, R2, R4, R5 and R6 each represent hydrogen and R3 represents fluoro.
In another additional embodiment, R2, R3, R5 and R6 each represent hydrogen and R4 represents: halogen (e.g., fluoro or chloro); CN; or C1.3 alkoxy (e.g., methoxy).
In a more particular embodiment R2, R3, R5 and R6 each represents hydrogen and R4 represents chloro, CN or methoxy.
In an alternative embodiment R2, R3, R5 and R6 each represents hydrogen and R4 represents fluoro.
In a further embodiment, R3, R5 and R6 each represent hydrogen, and R2 and R4 each represents fluoro.
In a further embodiment, R2, R5 and R6 each represents hydrogen, and R3 and R4 each represents fluoro.
In one embodiment, R7 and R8 independently represent hydrogen or methyl. In a more particular embodiment, R7 and R8 each represent hydrogen.
In one modality, A represents: pyridin-2-yl); pyridin-3-yl, wherein the pyridinyl ring may be optionally substituted in the 2-position by fluoro, methoxy or CH 2 OH, in the 4-position by methyl or CH 2 OH, or in the 5-position by fluoro; pyridazin-3-yl); pyridazin-4-yl); pyrimidin-5-yl); -1,3-oxazol-2-yl); 1 H-pyrazol-4-yl, wherein the pyrazolyl ring can be optionally substituted in the 1-position by methyl; isoxazol-4-yl, wherein the isoxazolyl ring may be optionally substituted in the 3-position by methyl or in the 5-position by methyl; or a group of formula a).
In a more particular modality, A represents: pyridin-3-yl, where the pyridinyl ring can be optionally substituted at position 2 by fluoro; pyridazin-4-yl); 1H-pyrazol-4-yl, wherein the pyrazolyl ring may be optionally substituted in the 1-position by methyl; or isoxazol-4-yl, wherein the isoxazolyl ring may be optionally substituted in the 3-position by methyl or in the 5-position by methyl.
In one embodiment, A represents pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, or a group of the formula a). In a more particular embodiment, A represents pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, or a group of the formula (a).
In one embodiment, A represents pyridin-3-yl, pyridazin-3-yl or pyridazin-4-yl, most particularly pyridin-3-yl.
In an alternative embodiment, A represents a group of formula (a).
In one embodiment, R9 represents: hydrogen; halogen (e.g., fluoro, chloro); C- | 2 alkyl (e.g., methyl, ethyl); C1-2 alkoxy (e.g., methoxy); -CH2CO2H, or -CONHCH3.
In a more particular embodiment, R9 represents hydrogen, halogen (e.g., fluoro chloro), C1.2 alkyl (e.g., methyl, ethyl) or C-i2 alkoxy (e.g., methoxy). Most particularly, R9 represents hydrogen, chlorine, methyl and methoxy.
In one modality: A represents pyridin-3-yl, pyridazin-4-yl, 1H-pyrazol-4-yl or isoxazoi-4-yl, wherein when A represents pyridin-3-yl, the pyridinyl ring may be optionally substituted in the position 2 by fluoro; when A represents 1 H-pyrazol-4-yl, the pyrazolyl ring may be optionally substituted at the 1-position by methyl, and where A represents isoxazol-4-yl, the isoxazolyl ring may be optionally substituted at the 3-position. by methyl or in the 5 position by methyl; R represents - (0) n (CH2) pR10, - (CO) R10, R13, - (S02) R13 or a nitrogen-containing heteroaryl ring said nitrogen-containing heteroaryl ring is optionally substituted by one, two or three groups selected from NH2, (C1-3 alkylene) R13, (Ci-3 alkylene) (CO) qR14, Ci-3 alkyl and halogen; R2, R3, R4, R5, R6 independently represent hydrogen or fluoro; R7 and R8 represent hydrogen; R 10 represents hydrogen, C 1-3 alkyl) -NR 11 R 12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups; R 1 and R 2 independently represent hydrogen or alkyl of C1.3); R 13 represents -NR R 12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached by a nitrogen atom; R 4 represents hydroxy or C 1-3 alkoxy; Y n and q independently represent 0 or 1 and p represents 1, 2 or 3; with the proviso that the compound of the formula (I) is not 2 - [(phenylmethyl) oxy] - / \ / - 3-pyridinyl-5- (1-pyrrolidinylsulfonyl) benzamide.
In a more particular embodiment, R1 represents - (CO) R10, wherein R10 represents hydrogen, C1.3 alkyl, -NR1 1R12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three groups methyl. Most particularly, R 1 represents - (CO) R 10, wherein R 0 represents hydrogen, C 3 alkyl, -NR 1 R 12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and said monocyclic ring is attached to the carbonyl group by means of a nitrogen atom.
In an alternative embodiment, R represents - (0) n (CH2) pR10, wherein R10 represents hydrogen, C1-3 alkyl, -NR1 R12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups, where n represents 0 or 1 and where p represents 1, 2 or 3. Very particularly, R represents - (0) n (CH2) pR °, wherein R 0 represents hydrogen, Ci-3 alkyl, -NR 1 R 12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups, wherein n represents 0 or 1 and wherein p represents 1.
In certain embodiments wherein R 1 represents - (O) n (CH 2) PR 10 or - (CO) R 10, R 0 represents a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups. Most particularly, R10 represents a nitrogen-containing monoheterocyclic ring selected from the group consisting of piperidinyl, piperazinyl pyrrolidinyl and morpholinyl, said ring is optionally substituted with one, two or three methyl groups.
Most particularly, R 0 represents: - piperidinyl (e.g., piperidin-1-yl or piperidin-4-yl) which is optionally substituted with one, two or three methyl groups; piperazinyl (e.g., piperazin-1-yl) which is optionally substituted with one, two or three methyl groups; pyrrolidinyl (e.g., pyrrolidin-1-yl or pyrrolidin-2-yl) which is optionally substituted with one, two or three methyl groups; or morpholinyl (e.g., morpholin-4-yl).
Most particularly still, R10 represents: unsubstituted piperidin-1-yl); piperidin-4-yl optionally substituted with one, two or three methyl groups (e.g., 1-methyl-piperidin-4-yl); piperazin-1-yl optionally substituted with one, two or three methyl groups (e.g., 4-methylpiperazin-1-yl) - unsubstituted pyrrolidin-1-yl); pyrrolidin-2-yl optionally substituted with one, two or three methyl groups (e.g., 1-methyl pyrrolidin-2-yl); or unsubstituted morpholin-4-yl.
In embodiments in which R1 represents - (CO) R10, R10 represents: unsubstituted piperidin-1-yl); piperidin-4-yl optionally substituted with one, two or three methyl groups (e.g., 1-methylpiperidin-4-yl); piperazin-1-yl optionally substituted with one, two or three methyl groups (e.g., 4-methylpiperazin-1-yl); unsubstituted pyrrolidin-1-yl); or unsubstituted morpholin-4-yl.
In other embodiments in which R 1 represents - (0) n (CH 2) p R 10 or - (CO) R 10, R 10 represents -NR 1 R 12, wherein R 1 and R 2 are independently selected from hydrogen and Ci 3 alkyl > wherein said C1.3 alkyl group is optionally substituted with one, two or three halogen, hydroxy, cyano or alkoxy groups of 0-2. Most particularly, R 11 and R 12 are independently selected from hydrogen and C 1-3 alkyl. Most particularly still, R1 and R12 are independently selected from hydrogen and methyl.
In a further embodiment, R represents R13 or - (S02) R13 wherein R13 represents -NR11R12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups and wherein the monoheterocyclic ring containing nitrogen is attached to sulfur by a nitrogen atom In a more particular embodiment, R represents R13, where R13 represents -NR11R12 or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached by a nitrogen atom.
In an alternative embodiment, R1 represents - (S02) R13, where R13 represents -NR1 R12 or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring it is bound to the sulfur by a nitrogen atom.
In certain embodiments wherein R1 represents R13 or - (S02) R13, R3 represents a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached by a nitrogen atom. Most particularly, R13 represents a nitrogen-containing monoheterocyclic ring selected from the group consisting of piperidinyl, piperazinyl pyrrolidinyl and morpholinyl, said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached by a nitrogen atom.
Most particularly still, R13 represents: - piperidinyl (e.g., piperidin-1-yl or piperidin-4-yl) which is optionally substituted with one, two or three methyl groups; piperazinyl (e.g., piperazin-1-yl) which is optionally substituted with one, two or three methyl groups; pyrrolidinyl (e.g., pyrrolidin-1-yl) which is optionally substituted with one, two or three methyl groups; or morpholinyl (e.g., morpholin-4-yl).
Most particularly still, R13 represents: unsubstituted piperidin-1-yl); piperidin-4-yl optionally substituted with one, two or three methyl groups (e.g., 1-methylpiperidin-4-yl); piperazin-1-yl optionally substituted with one, two or three methyl groups (e.g., 4-methylpiperazin-1-yl); unsubstituted pyrrolidin-1-yl); or unsubstituted morpholin-4-yl.
In other embodiments in which R1 represents R13 or - (S02) R13, R13 represents -NR 1R12, wherein R1 and R12 are independently selected from hydrogen and d-3 alkyl, wherein said Ci-3 alkyl group is optionally substituted with one, two or three groups halogen, hydroxy, cyano or Ci-2 alkoxy. Most particularly, R1 and R12 are independently selected from hydrogen and Ci-3 alkyl. Most particularly still, R 1 and R 12 are independently selected from hydrogen and methyl.
In a further embodiment, R1 represents a nitrogen-containing heteroaryl ring, said nitrogen-containing heteroaryl ring is optionally substituted by one, two or three groups selected from NH2, (C- | 3 alkylene), (Ci alkylene) -3) (CO) qR1 \ Ci-3 alkyl and halogen. Most particularly, R1 represents a nitrogen-containing heteroaryl ring, said nitrogen-containing heteroaryl ring is optionally substituted by a group selected from NH2, C-1.3R13 alkylene, (Ci.3 alkylene) (CO) qR14, alkyl of C1-3 and halogen.
Most particularly, R1 represents pyridinyl or pyrazolyl, said pyridinyl or pyrazolyl group is optionally substituted by one, two or three groups selected from NH2, (Ci.3 alkylene) R13, (alkylene from d-3) (CO) qR14, alkyl of Ci-3 and halogen. Most particularly, R 1 represents pyridinyl or pyrazolyl, pyridinyl or pyrazolyl group which is optionally substituted by a group selected from NH 2, alkylene of 3R 13, (C 1-3 alkylene) (CO) qR 14, C 1-3 alkyl and halogen.
Very particularly still, R represents: pyridin-4-yl optionally substituted by an NH2 or halogen group (e.g., 2-aminopyridin-4-yl, 2-fluoropyridin-4-yl); unsubstituted pyridin-3-yl); 1 H-pyrazol-4-yl optionally substituted by a group selected from 2- (4-morpholinyl)) ethyl, 2- (methyloxy) ethyl or methyl (e.g., 1 - [2- (4-morpholinyl)) ethyl] -1H-pyrazol-4-yl, 1- [2- (methoxy) ethyl] -1H-pyrazol-4-yl, 1-methyl-1 H-pyrazol-4-ito); or - 1 H-pyrazol-5-yl optionally substituted by a methyl group (e.g., 1 methyl-1 H-pyrazol-5-yl).
In certain embodiments, 2, R3, R4, R5 and R6 each represent hydrogen.
In certain embodiments, R2, R3, R5 and R6 each represent hydrogen and R4 represents fluoro.
In alternative embodiments, R3, R5 and R6 each represent hydrogen, and R2 and R4 each represent fluoro.
In alternative embodiments, R2, R5 and R6 each represent hydrogen, and R3 and R4 each represent fluoro.
The compounds of the formula (I) or salts thereof include the compound of Examples 1-137 and their salts. In a more particular embodiment, the compounds of the formula (I) or salts thereof include the compounds of examples 1-21 and 23-137, and their salts. Very particularly still, compounds of the formula (I) or salts thereof include the compounds of examples 1-21, 23-54, 57-61 and 63-137, and their salts In one embodiment, the compound of the formula (I) or a salt thereof is: 2-. { [(4-fluorophenyl) methyl] oxy} -5- (1-methyl-1 H-pyrazol-4-yl) -N-3- pyridinylbenzamide; 2-. { [(4-fluorophenyl) methyl] oxy]} -5- (1-methyl-1 H-pyrrazol-yl) -N-4-pyridazinylbenzamide; or a salt of it.
Other compounds of the formula (I) or salts thereof include: 2-. { [(4-fluorophenyl) methyl] oxy} -5- [3- (4-morpholinyl)) propyl)] - A / -3-pirtdinylbenzamide; or 2-. { [(4-fluorophenyl) methyl] oxy} -5-. { 1- [2- (4-morpholinyl)) ethyl] -1H-pyrazol-4-yl)} -A / -4-pyridazinylbenzamide; or a salt of it.
Certain compounds of the formula (I) are capable of forming salts. Specifically, where A represents pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-5-yl or H-pyrazol-4-yl (optionally substituted), wherein R 1 represents -O (CH 2) 20 (CH 2) 2NH2, or certain nitrogen-containing heteroaryl rings (optionally substituted), or wherein R10 represents a nitrogen-containing monoheterocyclic ring or a group -NR11R12, the compounds of the formula (I) may form acid addition salts. Said salts can be formed by reaction with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated for example by crystallization and filtration. Where A represents a group of the formula (a) and R9 represents -CH2CO2H, or where R14 represents hydroxy, the compounds of the formula (I) can form basic salts. Said salts can be formed by reaction with the appropriate base, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated for example by crystallization and filtration.
Due to their potential use in medicine, the salts of the compound of the formula (I) are preferably pharmaceutically acceptable.
The pharmaceutically acceptable acid addition salts of the compounds of the formula (I) include salts of hydrobromide, hydrochloride, sulfate, nitrate, phosphate, succinate, maleate, formate, acetate, propionate, fumarate, citrate, tartrate, lactate, benzoate, salicylate. , glutamate, aspartate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate) or hexanoate.
The pharmaceutically acceptable basic addition salts of the compounds of the formula (I) include metal salts (such as sodium, potassium, aluminum, calcium, magnesium and zinc salts) and ammonium salts (such as isopropylamine, diethylamine salts, diethanolamine).
The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of the formula (I).
Certain compounds of the formula (I) or salts thereof may exist in the form of solvates (e.g., hydrates).
Certain compounds of the formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of these compounds and mixtures thereof including racemates. The different stereoisomeric forms they can be separated from one another by methods known in the art (e.g., separation by chiral HPLC), or any given isomer can be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.
The invention also includes compounds and salts isotopically, which are identical to compounds of the formula (I) or salts thereof, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the formula (I) or salts of the same isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3H, 11C, 14C and 18F. Said isotopically labeled compounds of the formula (I) or salts thereof are useful in tests of drug distribution and / or substrate tissue. For example, isotopes 11C and 18F are particularly useful in PET (positron emission tomography). PET is useful in brain imaging. The isotopically-labeled compounds of the formula (I) and salts thereof can generally be prepared by carrying out the procedures described below, by using an easily available isotopically-labeled reagent in place of a non-isotopically labeled reagent. In one embodiment, the compounds of the formula (I) or salts thereof are not isotopically labeled.
When used in therapy, a compound of the formula (I) or pharmaceutically acceptable salt thereof is usually formulated in a standard pharmaceutical composition. Said compositions can be prepared using standard procedures.
The present invention further provides a pharmaceutical composition comprising the compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
When a compound of the formula (I) or a pharmaceutically acceptable salt thereof is designed for use in the treatment of Parkinson's disease, it can be used in combination with drugs that are considered to be useful as symptomatic treatment of Parkinson's disease. Suitable examples of these other therapeutic agents include L-dopa, and dopamine agonists (e.g., pramipexole, ropinirole).
When a compound of the formula (I) or a pharmaceutically acceptable salt thereof is designed for use in the treatment of Alzheimer's disease, it can be used in combination with medications that are considered to be useful either as modification treatments or as symptomatic of Alzheimer's disease. Suitable examples of these other therapeutic agents may be symptomatic agents, for example those known to modify cholinergic transmission such as muscarinic agonists, M1, allosteric modulators, M2 muscarinic antagonists, acetylcholinesterase inhibitors (such as tetrahydroaminoacridine, donepezil hydrochloride and rivastigmine). ), nicotinic receptor agonists or allosteric modulators (such as a7 agonists or allosteric modulators or a4ß2 agonists or allosteric modulators), PPAR agonists (such as PPARy agonites), partial 5-HT4 receptor agonists, receptor antagonists 5-HT6 or 5HT1A receptor antagonists and NMDA receptor antagonists or modulators, or disease modifying agents such as β- or β-secretase inhibitors, mitochondrial stabilizers, microtubule stabilizers or Tau pathology modulators such as aggregation inhibitors of Tau (e.g., methyl blue eno and REMBER ™).
When a compound of the formula (I) or a pharmaceutically acceptable salt thereof is used in combination with other therapeutic agents, the compounds can be administered either sequentially or simultaneously by any convenient route.
The invention therefore provides, in a further aspect, a combination comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof, together with an additional therapeutic agent or agents.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and therefore pharmaceutical formulations comprising a combination as defined above, together with a pharmaceutically acceptable carrier or excipient, comprise a further aspect of the invention. The Individual components of said combinations can be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
When a compound of the formula (I) or a pharmaceutically acceptable salt thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. The appropriate doses will be readily appreciated by those skilled in the art.
The pharmaceutical compositions can be administered to patients by any convenient route. For example, pharmaceutical compositions include those adapted for (1) oral administration such as tablets, capsules, caplets, pills, pills, powders, syrups, elixirs, suspensions, solutions, emulsions, sacks and cachets; (2) parenteral administration such as solutions, suspensions, implants and sterile powders for reconstitution; (3) transdermal administration such as transdermal patches; (4) by inhalation and intranasal such as dry powders, aerosols, suspensions and solutions (sprays and drops); (5) buccal and sublingual administration such as pills, patches, sprays, drops, chewing gums and tablets. Orally administrable pharmaceutical compositions are generally preferred.
The compounds of the formula (I) or pharmaceutically acceptable salt thereof can be moles using methods of known grinding such as wet milling to obtain an appropriate particle size for tabletting and for other types of formulation. The finely divided preparations (nanoparticles) of the compounds of the invention can be prepared by procedures known in the art, for example WO 02/00196.
Tablets and capsules for oral administration may be in unit dose form, and may contain conventional carriers, such as diluents, binding agents, lubricants, disintegrants, slippers, granulating agents, coating agents and wetting agents. The person skilled in the art will appreciate that certain pharmaceutically acceptable excipients may have more than one function and may have alternative functions depending on how much of the excipient is present in the formulation and what other ingredients are present in the formulation. The tablets can be coated according to methods well known in normal pharmaceutical practice.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the severity of the disorders, the weight of the patient, and other similar factors. However, as a general guide, suitable compositions will contain 0.1 to 1000 mg, very suitably 0.1 to 200 mg and most suitably still 1.0 to 200 mg of the compound of the formula (I) or a pharmaceutically acceptable salt thereof and 0.1 to 2. g of one or more pharmaceutically acceptable vehicles. Said pharmaceutical compositions can be administered more than once a day, for example two or three times a day. This therapy can be extended for several weeks, months or years.
The present invention also provides a process for the preparation of a compound of the formula (I) or a salt thereof, said process comprising: a) reacting a compound of the formula (II) or a salt thereof: wherein R2, R3, R4, R5, R6, R7 and R8 are as defined above, and wherein R1 is as defined above, with the proviso that R14 is not hydroxy, with an A-NH2 or a salt of the same; or b) reacting a compound of the formula (VI) or a salt thereof: (SAW) wherein A is as defined above, wherein R1 is as defined above with the proviso that R1 is not hydroxy, with a compound of the formula (IV) or a salt thereof: wherein R2, R3, R4, R5, R6, R7 and R8 are as defined above and wherein l_i is a suitable residual group, such as a halogen group (e.g., bromine) or a hydroxy group; c) reacting a compound of the formula (VII) or a salt thereof: wherein R2, R3, R4, R5, R6, R7 and R8 are as defined above, wherein R1 is as defined above with the proviso that R14 is not hydroxyl, and wherein P1 represents a suitable protecting group such as methyl, with A-NH2 or a salt thereof; or d) interconversion of a compound of the formula (I) or a salt thereof to another compound of the formula (I), or a salt thereof; or e) deprotection of a compound of the formula (I) or a salt thereof that is protected.
Process (a) typically utilizes activating agents such as 1- (3-dimethylaminopropyl)) - 3-ethylcarbodiimide hydrochloride (EDC) together with 1-hydroxybenzotriazole (HOBT), or HATU, or CDI (A7, / V-carbonyl) diimidazole) in a suitable solvent at a suitable temperature. Where EDC / HOBT is used, the reaction may optionally take place in the presence of a base (e.g., triethylamine, diisopropyl) ethylamine or N-ethylmorpholine). Suitable solvents for this reaction include dichloromethane (DC) or dimethylformamide (DMF) and a suitable temperature would be, e.g., between 15 ° C and 40 ° C. Where CDI is used, a suitable solvent would be THF (tetrahydrofuran). The reaction is a two step process wherein the reaction of CDI with the acid is carried out at a suitable temperature such as room temperature, followed by addition of the amine with stirring at a suitable temperature e.g., reflux. Where HATU is used, the reaction may optionally take place in the presence of a base (e.g., diisopropylethylamine). Suitable solvents for this reaction include dimethylformamide (DMF) and a suitable temperature would be, e.g., room temperature.
Alternatively, process (a) may comprise a step of converting the compound of formula (II) into the corresponding acyl chloride, followed by reaction with A-NH2 or a salt thereof. The step of converting the compound of the formula (II) to an acyl chloride typically comprises treating the compound of the formula (II) with oxalyl chloride in a suitable solvent (e.g., DCM in the presence of a catalytic amount). of DMF) at a suitable temperature (e.g., room temperature). The step of reacting the acyl chloride with A-NH2 or a salt thereof optionally takes place in the presence of a base (e.g., diisopropyl) ethylamine or triethylamine) in a suitable solvent such as DCM, at a suitable temperature v.gr., between room temperature and 40 ° C.
When I-? is a hydroxyl group, process (b) is a two-step procedure. The first step is the formation of a basic salt by treating the compound of the formula (VI) with a base (e.g., potassium hydroxide) in a suitable solvent (such as methanol), at a suitable temperature (such as room temperature). The second step involves the addition of the compound of the formula (IV) and takes place in a suitable solvent (such as DMF) at a suitable temperature, such as reflux. Alternatively, when U is a hydroxy group, process (b) can take place in the presence of coupling agents such as DEAD (diethyl azodicarboxylate) or DIAD (diisopropyl azodicarboxylate), and Ph3P (triphenyl phosphine). The reaction takes place in a suitable solvent such as toluene or DCM at a suitable temperature such as from 0 ° C to room temperature.
When l_i is halogen (e.g., bromine), process (b) typically takes place in the presence of a base such as potassium carbonate or cesium carbonate, in a suitable solvent (e.g., DMF or acetone) at a suitable temperature (e.g., between ambient temperature and reflux).
Process (c) can be used where the acid is unstable and requires protect For certain compounds of the formula (VII), process (c) is a one-step process that is conducted as described above for process (a). For other compounds, process (c) can be a two-step procedure. The first step comprises treatment with potassium trimethylsilanolate. The second step comprises reactwith A-NH2 or a salt thereof. This step can be conducted as described above for procedure (a).
Process (d) uses standard chemical transformat known to one skilled in the art.
The compounds of the formula (I), wherein R represents: a monoheterocyclic ring containing -O-nitrogen with the proviso that the atom directly attached to oxygen is not nitrogen; or - (0) n (CH2) pR10, where n represents 1, p represents 1, 2 or 3 and R10 represents -NR 1R12, or a nitrogen-containing monoheterocyclic ring, said ring is optlly substituted with one, two or three groups methyl; it can be prepared by reactof the corresponding compound of the formula (I) wherein R 1 represents hydroxy with the corresponding alcohol. This reacttypically occurs in the presence of coupling agents such as DIAD (diisopropyl azodicarboxylate) and Ph3P (triphenylphosphine) in a suitable solvent such as toluene, at a suitable temperature such as 1 15 ° C.
The compounds of the formula (I) wherein R1 represents - (0) n (CH2) pR10, wherein n represents 0, p represents 1 and R10 represents -NR 1R12, or a nitrogen-containing monoheterocyclic ring, said ring is optlly substituted with one, two or three methyl groups and said ring is attached to the carbon by a nitrogen atom, it can be prepared by reactof the corresponding compound of the formula (I) wherein R 1 represents COR 10, wherein R 10 represents hydrogen (i.e. , formyl)) by reductive alkylatof the corresponding amine. The reactutilizes a reducing agent (e.g., sodium triacetoxyborohydride) optlly in the presence of an acid (e.g., acetic acid) in a suitable solvent such as DCE at a suitable temperature such as 50 ° C.
The compounds of the formula (I) wherein R 1 represents -CNOH can be prepared from compounds of the formula (I), wherein R 1 represents - (CO) R 10, wherein R 10 represents hydrogen (ie, formyl) per reactwith hydroxylamine hydrochloride. This reacttypically occurs in the presence of a base (e.g., pyridine) in a suitable solvent (e.g., methanol) at a suitable temperature (e.g., room temperature).
The compounds of the formula (I) wherein R represents R13 can be prepared by reactof the corresponding compound of the formula (I) wherein R1 represents halogen (e.g., bromine) with the corresponding amine in the presence of coupling agents such as such as 2,2'-bis (diphenylphosphino) -1, 1'-biphenyl and tris (dibenzylidene ketone) dipalladium (0). The reactoptlly takes place in the presence of a base such as cesium carbonate. The reacttakes place in a suitable solvent such as toluene, at a suitable temperature, such as reflux.
The compounds of the formula (I) wherein R 1 represents a nitrogen-containing heteroaryl ring, said nitrogen-containing heteroaryl ring is optlly substituted by one, two or three groups selected from NH 2, (alkylene of C- | .3) R13, (C1.3 alkylene) (CO) qR14, C1-3 alkyl and halogen can be prepared by reactof the corresponding compound of the formula (I) wherein R1 represents halogen (e.g., bromine) with the composed of corresponding boronic acid or dioxoborlane.
Where the boronic acid is used, the reaction takes place in the presence of a suitable coupling agent such as tetrakis (triphenylphosphino) palladium (0) or bis (triphenylphosphino) palladium chloride (11) optionally in the presence of a base, such as carbonate of sodium. The reaction takes place in a suitable solvent (such as D E or 4-dioxane) and at a suitable temperature such as 100-140 ° C.
Where the corresponding dioxoborolane is used, the reaction it occurs in the presence of a suitable coupling agent such as tetrakis (triphenylphosphino) palladium (0), optionally in the presence of a base, such as sodium carbonate or tripotassium phosphate. The reaction takes place in a suitable solvent (such as DME or 1,4-dioxane) at a suitable temperature such as 80-140 ° C.
The person skilled in the art will also appreciate that where R is pyrazol-4-yl or pyrazol-5-yl substituted by (Ci-3 alkylene) R13 or (Ci-3 alkylene) (CO) qR14, these compounds can be prepare from the corresponding unsubstituted compound by reaction with a compound of the formula Z- (alkylene of Ci.3) R13 or Z- (alkylene of Ci-3) (CO) qR14 wherein Z is halogen. The reaction typically takes place in the presence of a suitable base such as potassium carbonate at a suitable temperature, such as 50 ° C.
The compounds of the formula (I) and salts thereof wherein R represents: (CH = CH) (CO) R14 wherein R14 represents alkoxy of d3; (C2-3 alkylene) (CO) qR14 wherein the alkylene is a straight chain alkylene, q is 1 and R4 represents hydroxy or Ci-3 alkoxy; (C2-3 alkylene) (CO) qR14 wherein the alkylene is a straight chain alkylene, q is 0 and R14 represents hydroxy; or (C2-3 alkylene) (CO) qR14 wherein the alkylene is a straight chain alkylene and R14 represents C ^ alkoxy; it can be prepared from compounds of the formula (I) wherein R represents halogen in the same manner as described in Scheme 3 in relation to compounds of the formula (VII).
The compounds of the formula (I) of salts thereof wherein R represents (CH = CH) C02CH2CH3 can alternatively be prepared by reaction of the corresponding compound of the formula (I) wherein R represents COR10, wherein R 0 represents hydrogen (ie, formyl) with KHMDS and triethyl phosphonoacetate. The reaction takes place in a suitable solvent such as tetrahydrofuran, at a suitable temperature such as -78 ° C.
The compounds of the formula (I) or salts thereof wherein R 1 is (C 1-3 alkylene) (CO) q R 14 wherein the alkylene group is CH 2, CH (CH 3), CH 2 CH (CH 3) or C (CH 3) 2, wherein q is 0 or 1 and R14 represents hydroxy, can be prepared as described in steps (xiii) and (xiv) of scheme 3 from the corresponding ester. Alternatively, the compounds of the formula (I) or salts thereof wherein R1 represents CH (CH3) (CO) qR14, q represents 0 and R14 represents hydroxy, can be prepared by reduction of the corresponding aldehyde (e.g. the corresponding compound of the formula (I) wherein R 1 represents COR 10, wherein R 0 represents hydrogen (ie, formyl)). Sodium borohydride can be used as a reducing agent in a suitable solvent such as ethanol at a suitable temperature such as room temperature. The reaction may optionally take place in the presence of an acid, e.g., boric acid. Similarly, the compounds of the formula (I) or salts thereof wherein R 1 represents (alkylene of Ci-3) (CO) qR 14, q represents 0 and R 14 represents hydroxy, can be prepared by reaction of the corresponding aldehyde (e.g., the corresponding compound of the formula (I) wherein R 1 represents COR 10, wherein R 10 represents hydrogen (ie, formyl)) with methylmagensium bromide. The reaction takes place in a suitable solvent such as THF at a suitable temperature such as between 0 ° C and room temperature.
The compounds of the formula (I) or salts thereof wherein R is (C 1-3 alkylene) NHCOR 14 wherein the alkylene group is CH 2, CH (CH3), CH2CH (CH3) or C (CH3) 2 and wherein R14 represents d-3 alkoxy can be prepared as described in steps (x) to (xii) from the corresponding ester. Alternatively, the compounds of the formula (I) wherein R 1 represents (Ci-3 alkylene) NHCOR 14 wherein the alkylene is CH 2 and R 14 represents -O 3 C 1-3 alkyl can be prepared from compounds of the formula (I) wherein R1 represents -CNOH in a two-step process. First, the amine is generated by treatment with zinc in the presence of acid (e.g., HCI). The reaction takes place in a suitable solvent e.g., THF at a suitable temperature e.g., 60 ° C. The amine is then reacted with a compound of the formula L2-CO2alkyl of C -3 wherein L2 is halogen. The reaction takes place at a suitable temperature such as room temperature. The compounds of the formula (I) wherein R 1 represents (Ci-3 alkylene) NHCOR 14 wherein the alkylene is CH (CH 3) and R 14 represents -O-C 1-3 alkyl can be prepared from corresponding compounds wherein R 1 represents -C (CH3) NOH in a similar manner. Compounds wherein R 1 represents -C (CH 3) NOH can be prepared from compounds of the formula (I) wherein R 1 represents - (CO) R 10, wherein R 10 represents methyl by reaction with hydroxylamine hydrochloride. This reaction typically occurs in the presence of a base (e.g., pyridine) in a suitable solvent (e.g., methanol) at a suitable temperature (e.g., room temperature).
The compounds of the formula (I) wherein R 1 represents (Ci-3 alkylene) (CO) qR 14, q represents 0 and R 14 represents hydroxy, can be prepared by reaction of the corresponding compound of the formula (I) wherein R represents (Ci-3 alkylene) (CO) qR14, q represents 0 and R 4 represents -OC -3alkyl by treatment with lithium hydroxide in a suitable solvent such as a mixture of THF and water, at a suitable temperature such as room temperature.
Similarly, the compounds of the formula (I) wherein R 1 represents (CH = CH) (CO) R 14 or (C 1-3 alkylene) NHCOR 14 wherein R 4 represents hydroxy can be prepared by reaction of the corresponding compound of the formula (I) wherein R1 represents (CH = CH) (CO) R14 or (Ci_3 alkylene) NHCOR14, wherein R4 represents -Ci-3alkyl by treatment with lithium hydroxide in a suitable solvent such as a mixture of THF and water, at a suitable temperature such as room temperature.
The compounds of the formula (I) or salts thereof wherein R1 represents - (S02) R13 wherein R13 represents -NR11R12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached to the sulfur by a nitrogen atom, it can be prepared from compounds of the formula (I) wherein R 1 represents halo in the same manner as described in steps (xviii) and (xix) of scheme 5.
The compounds of the formula (I) or salts thereof wherein R 1 represents - (CO) R 10 wherein R 10 represents -NR 11 R 12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and said monocyclic ring is attached to the carbonyl group by means of a nitrogen atom, they can be prepared from the corresponding compounds in which R is a carboxylic acid. This procedure can be carried out as described above for process (a). The carboxylic acid compounds can be prepared from the corresponding compounds of the formula (I) wherein R 1 represents COR 10, wherein R 10 represents hydrogen (ie, formyl) by treatment with potassium permanganate. This reaction takes place in a suitable solvent such as acetone at a suitable temperature such as room temperature.
Process (e) is a deprotection reaction and the nature of the reaction will depend on the protecting group. When an amine is protected by a protecting group such as 1,1-dimethylethyl carboxylate, the deprotection comprises treatment with trifluoroacetic acid in a suitable solvent (e.g., DCM) at a suitable temperature eg, between room temperature and 30 ° C. When an acid group is protected by a protecting group such as methyl, deprotection may comprise treatment with lithium hydroxide in a suitable solvent such as a mixture of THF and water, at a suitable temperature such as room temperature.
The compounds of the formula (II) or salts thereof, compounds of the formula (VI) or salts thereof and compounds of the formula (VII) or salts thereof wherein R 1 represents: -halogen; -halogenalkyl of Ci-3¡ -CN, - (CO) R10 wherein R10 represents hydrogen, Ci-3 alkyl, -NR 1R12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups; - (0) n (CH2) pR10 wherein n represents 0 or 1, p represents 1, 2 or 3 and R 0 represents hydrogen or C1.3 alkyl); or - (0) n (CH2) pR10 wherein n represents 0, p represents 1, 2 or 3 and R 0 represents -NR11R12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups; They can be prepared in accordance with the following procedure: SCHEME 1 wherein, A, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined above and wherein Pi represents a suitable protecting group, such as methyl.
Step (i) can be carried out as described above for process (b).
Step (ii) typically comprises treating a compound of the formula (III) with lithium hydroxide in a suitable solvent, such as a mixture of THF (tetrahydrofuran) and water or a mixture of THF, methanol and water, to a suitable temperature such as between room temperature and reflux. Alternatively, step (ii) may comprise refluxing in a mixture of ethanol and 2M NaOH.
The step (ü) can be carried out as described above for process (a).
Step (iv) is a protection step. The nature of this reaction will depend on the protecting group. Where Pi represents methyl, this step comprises reaction with methanol, optionally in the presence of an acid (e.g., sulfuric acid).
The compounds of the formula (VI) or salts thereof in which R 1 is (C 1-3 alkylene) (CO) q R 14 wherein q represents 0 or 1 and R 14 represents C 1-3 alkoxy can also be prepared as described in step (iii) from the corresponding compound of the formula (V). The compound of the formula (V) can be prepared according to the following procedure: SCHEME 2 (VIII) (V) wherein R1 is (Ci-3 alkylene) (CO) qR14, q represents 0 or 1 and represents C1.3 alkoxy.
Step (v) is a two-step reaction. The first step it comprises reaction with paraformaldehyde in the presence of a base such as triethylamine and a suitable solvent such as acetonitrile at a suitable temperature such as reflux. The second step comprises treatment with potassium permanganate The compounds of the formula (III) wherein R represents - (0) n (CH2) pR10, wherein n represents 0, p represents 1 and R 0 represents -NR11R12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and said ring it is attached to the carbon by a nitrogen atom, it can be prepared by reaction of the corresponding compound of the formula (III) wherein R 1 represents COR 10, wherein R 0 represents hydrogen (ie, formyl) by reductive alkylation of the corresponding amine. The reaction utilizes a reducing agent (e.g., sodium triacetoxyborohydride) optionally in the presence of an acid (e.g., acetic acid) in a suitable solvent such as DCE at a suitable temperature such as 50 ° C.
The compounds of the formula (VII) wherein R. represents - (O) n (CH2) pR10, wherein n represents 0, p represents 3 and R10 represents -NR11R12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups and said ring is attached to the carbon by a nitrogen atom, it can be prepared by reaction of the corresponding compound of the formula (VII) wherein R represents halogen in a three-step process. The first step comprises reaction with 3,3-bis (ethyloxy) -1-propene and takes place in the presence of a palladium acetate catalyst, optionally in the presence of a base such as potassium carbonate. A suitable solvent is DMF and a suitable temperature is 120 ° C. The second step comprises reductive alkylation of the corresponding amine. The reaction utilizes a reducing agent (e.g., sodium triacetoxyborohydride) optionally in the presence of an acid (e.g., acetic acid) in a suitable solvent such as DCE at a suitable temperature such as room temperature. The third step comprises hydrogenating the double bond using hydrogen in the presence of Pd / C in methanol.
The compounds of the formula (III) wherein R represents -CNOH can be prepared from compounds of the formula (III) wherein R 1 represents - (CO) R 10, wherein R 10 represents hydrogen (ie, formyl) by reaction with hydroxylamine hydrochloride. This reaction typically occurs in the presence of a base (e.g., pyridine) in a suitable solvent (e.g., methanol) at a suitable temperature (e.g., room temperature).
The compounds of the formula (III) wherein R represents R13 can be prepared by reaction of the corresponding compound of the formula (III) wherein R1 represents halogen (e.g., bromine) with the corresponding amine in the presence of coupling agents such as 2,2-bis (diphenylphosphino) -1, 1'-biphenyl and tris (dibenzylideneacetone) dipalladium (0). The reaction optionally takes place in the presence of a base such as cesium carbonate. The reaction takes place in a suitable solvent such as toluene, at a suitable temperature, such as reflux.
The compounds of the formula (III) wherein R represents a nitrogen-containing heteroaryl ring, said nitrogen-containing heteroaryl ring is optionally substituted by one, two or three groups selected from NH2, (alkylene of C- | .3) R13, (Ci.3 alkylene) (CO) qR14, C1.3 alkyl and halogen can be prepared by reaction of the corresponding compound of the formula (III) wherein R1 represents halogen (e.g., bromine) with the composed of corresponding boronic acid or dioxoborlane.
Where the boronic acid is used, the reaction takes place in the presence of a suitable coupling agent such as tetrakis (triphenylphosphino) palladium (0) or bis (triphenylphosphino) palladium chloride (11) optionally in the presence of a base, such as carbonate of sodium. The reaction takes place in a suitable solvent (such as DME or 1,4-dioxane) and at a suitable temperature such as 100-140 ° C.
Where the corresponding dioxoborolane is used, the reaction takes place in the presence of a suitable coupling agent such as tetrakis (triphenylphosphino) palladium (0), optionally in the presence of a base, such as sodium carbonate or tripotassium phosphate. The reaction takes place in a suitable solvent (such as DME or 1,4-dioxane) at a suitable temperature such as 80-140 ° C.
The person skilled in the art will also appreciate that where R 1 is pyrazol-4-yl or pyrazol-5-yl substituted by (Ci-3 alkylene) R 13 or (C- | 3 alkylene) (CO) qR 14, these compounds can be prepared from the corresponding unsubstituted compound by reaction with a compound of the formula Z- (C -3 alkylene) R13 or Z- (Ci-3 alkylene) (CO) qR14 wherein Z is halogen. The reaction typically takes place in the presence of a suitable base such as potassium carbonate at a suitable temperature, such as 50 ° C.
The compounds of the formula (III) or salts thereof wherein R 1 represents (CH = CH) C 0 2 CH 2 CH 3 can alternatively be prepared by reaction of the corresponding compound of the formula (III) wherein R 1 represents COR 10, wherein R 0 represents hydrogen (ie, formyl) with KHMDS and triethyl phosphonoacetate. The reaction takes place in a suitable solvent such as tetrahydrofuran, at a suitable temperature such as -78 ° C.
The compounds of the formula (III) or salts thereof wherein R represents CH (CH 3) (CO) qR 14, q represents 0 and R 14 represents hydroxy can be prepared by reduction of the corresponding aldehyde (e.g., the corresponding compound of the formula (III) wherein R1 represents COR10, wherein R10 represents hydrogen (ie, formyl)). Sodium borohydride can be used as a reducing agent in a suitable solvent such as ethanol at a suitable temperature such as room temperature. The reaction may optionally take place in the presence of an acid, e.g., boric acid.
The compounds of the formula (III) wherein R represents (Ci-3 alkylene) NHCOR14 wherein the alkylene is CH2 and R14 represents -Ci-3alkyl can be prepared from compounds of the formula (III) wherein R1 represents -CNOH in a two-step process. First, the amine is generated by treatment with zinc in the presence of acid (e.g., HCI). The reaction takes place in a suitable solvent, e.g., THF at a suitable temperature e.g., 60 ° C. The amine is then reacted with a compound of the formula L2-C02 C1-3alkyl wherein L2 is halogen. The reaction takes place at a suitable temperature such as room temperature. The compounds of the formula (III) wherein R 1 represents (Ci-3 alkylene) NHCOR 14 wherein the alkylene is CH (CH 3) and R 4 represents -O-C 1-3 alkyl can be prepared from corresponding compounds in where R1 represents -C (CH3) NOH in a similar manner. The compounds wherein R represents -C (CH 3) NOH can be prepared from compounds of the formula (III) wherein R 1 represents - (CO) R 10, wherein R10 represents methyl by reaction with hydroxylamine hydrochloride. This reaction typically occurs in the presence of a base (e.g., pyridine) in a suitable solvent (e.g., methanol) at a suitable temperature (e.g., room temperature).
The compounds of the formula (III) or salts thereof wherein R 1 represents - (S02) R 13 wherein R 3 represents -NR 11 R 12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached to the sulfur by a nitrogen atom, it can be prepared from compounds of the formula (III) wherein R 1 represents halogen in the same manner as described in the steps (xviii) and (xix) of scheme 5.
The compounds of the formula (III) or salts thereof wherein R 1 represents - (CO) R 10 wherein R 10 represents -NR 11 R 12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and said monocyclic ring is attached to the carbonyl group by means of a nitrogen atom, they can be prepared from the corresponding compounds in which R1 is a carboxylic acid. This procedure can be carried out as described above for process (a). The carboxylic acid compounds can be prepared from the corresponding compounds of the formula (III) wherein R 1 represents COR 10, wherein R 10 represents hydrogen (ie, formyl) by treatment with potassium permanganate. This reaction takes place in a suitable solvent such as acetone at a suitable temperature such as room temperature.
The compounds of the formula (VII) or salts thereof wherein R 1 represents: (CH = CH) (CO) R14 wherein R14 represents O-alkyl of C1.3); (Ci.3 alkylene) (CO) qR14 wherein the alkylene is a straight chain alkylene, q is 1 and R14 represents OH or Ci_3 Oalkyl); (C2-3 alkylene) (CO) qR14 wherein the alkylene is a straight chain alkylene, q is 0 and R14 represents OH; or (C2-3 alkylene) NHCOR14 wherein the alkylene is a straight chain alkylene and R4 represents Ci_3 O-alkyl); it can be prepared from the corresponding compound of the formula (VII) wherein R 1 represents halogen according to the following procedure: SCHEME 3 alkyl of R1 alkylene of C2-3 NHCOR14 (R14 = 0 alkyl of C- | _3. R = 0, wherein? ,, A, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined above, wherein X represents C1.3 alkyl or tert-butyl and wherein r represents 0 or 1.
Step (vi) comprises reaction with a compound of the formula (IX). This step typically takes place in the presence of a palladium (O) catalyst such as palladium acetate and in the presence of a base such as potassium carbonate in a suitable solvent such as α, β-dimethylformamide at a suitable temperature such as 90 °. C.
Step (vii) comprises hydrogenating the double bond and optionally substituted benzyl ether using hydrogen in the presence of Pd / C in methanol.
The steps (viii) and (ix) can be carried out as described above for the process (b).
Step (x) is a Curtius reaction comprising reaction of the acid with diphenylphosphorylazide in the presence of base such as triethylamine in a suitable solvent such as a toluene / tert-butanol mixture.
Step (xi) comprises deprotection of the tert-butyl ester by treatment with trifluoroacetic acid in a suitable solvent such as dichloromethane.
Step (xii) comprises reaction with the appropriate acid. This step can be carried out as described above for process (a).
Step (xiii) is a deprotection reaction and comprises the treatment with trifluoroacetic acid in a suitable solvent (e.g., DCM) at a suitable temperature e.g., between room temperature and 30 ° C.
Step (xiv) comprises coupling the acid to give a mixed anhydride using isobutyl chloroformate in the presence of a base (N-methylmorpholine) in a suitable solvent such as tetrahydrofuran. The mixed anhydride is then reduced in situ using sodium borohydride.
The compounds of the formula (VII) or salts thereof wherein R 1 is (C 1-3 alkylene) (CO) q R 14 wherein the alkylene group is CH 2, CH (CH 3), CH 2 CH (CH 3) or C (CH 3) 2, wherein q is 0 or 1 and R14 represents OH can be prepared as described in steps (xiii) and (xiv) from the corresponding compound of the formula (XI).
The compounds of the formula (VII) or salts thereof wherein R 1 is (C 1-3 alkylene) NHCOR 14 wherein the alkylene is CH 2, CH (CH 3), CH 2 CH (CH 3) or C (CH 3) 2 and wherein R 4 represents Ci-3 -alkyl can be prepared as described in steps (xi) to (xii) from the corresponding compound of the formula (XII).
The compounds of the formula (VII) wherein R 1 represents (CH = CH) C 0 2 CH 2 CH 3 can alternatively be prepared by reaction of the corresponding compound of the formula (VII) wherein R 1 represents COR 10, wherein R 0 represents hydrogen (ie formyl) ) with KHMDS and triethyl phosphonoacetate. The reaction takes place in a suitable solvent such as tetrahydrofuran, at a suitable temperature such as -78 ° C, The compounds of the formula (II) or salts thereof in where R1 represents hydroxyl, it can be prepared according to the following procedure: SCHEME 4 wherein R2, R3, R4, R5, R5, R7 and R8 are as defined above.
Step (xv) comprises reaction with TsCI, optionally in the presence of a base such as potassium carbonate. The reaction takes place in a suitable solvent such as acetone, at a suitable temperature, such as reflux.
Step (xvi) can be carried out as described above for process (b).
Step (xvii) is a step of deprotection and varies depending on the nature of P ^. Where Pi is methyl, this step may comprise boiling with potassium hydroxide in a suitable solvent, e.g., mixture of ethanol and water.
The compounds of the formula (II) wherein R 1 represents: monoheterocyclic ring containing -O-nitrogen with the proviso that the atom directly attached to oxygen is not nitrogen; or - (0) n (CH2) pR10, where n represents 1, p represents 1, 2 or 3 and R10 represents -NR1 1R12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three groups methyl; it can be prepared by reaction of the corresponding compound of the formula (II) wherein R represents hydroxy with the corresponding alcohol. This reaction typically occurs in the presence of coupling agents such as DIAD (azodicarboxylate diisopropyl) and Ph3P (triphenylphosphine) in a suitable solvent such as toluene, at a suitable temperature such as 1 15 ° C.
The compounds of the formula (II) wherein R 1 represents hydroxyl can be used to prepare compounds of the formula (II) wherein R 1 represents (0) n (CH 2) p R 10, wherein n represents 0, p represents 1, 2 or 3 and R10 represents -NR 1 R 12 or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups. Where R10 is not a tertiary amine, the nitrogen will need to be protected during the reaction with a suitable protecting group (e.g., 1,1-dimethylethyl carboxylate). The reaction is a two-step procedure. In the first step, the compound of the formula (II) wherein R 1 represents hydroxyl is treated with sodium hydride in a suitable solvent such as DMSO at a suitable temperature such as room temperature. The second step comprises reaction with L3- (CH2PPR10, wherein R10 and p are as defined above and L3 represents a suitable residual group such as 4-methybenzenesulfonate or 4-chlorophenylsulfonyloxy.This step takes place in a suitable solvent such as DMSO at a suitable temperature such as 75 ° C. Any protecting groups can be removed in this step to generate a compound of the formula (II), or after reaction with a compound of the formula A-NH2 (to generate a compound of the formula I)). Where the protecting group is 1,1-dimethylethyl carboxylate, it can be removed by treatment with trifluoroacetic acid.
The compounds of the formula (II) wherein R 1 represents hydroxyl can be used to prepare compounds of the formula (II) wherein R represents -O (CH 2) 2 O (CH 2) 2 NH 2. The primary amine will need to be protected during the reaction with a suitable protecting group (e.g., 1,1-dimethylethyl carboxylate). The reaction is a two-step procedure. In the first step, the compound of the formula (II) wherein R1 represents hydroxyl is treatment with 2,2-oxybis (ethane-2, 1-diyl)) bis (4-methylbenzenesulfonate). The reaction with 2,2-oxybis (ethane-2,1-diyl)) bis (4- methylbenzene sulfonate) takes place in the presence of a suitable base such as potassium hydroxide in a suitable solvent such as methanol. The second step comprises reaction with the protected amine. The reaction with the protected amine occurs in the presence of a base such as cesium carbonate in a suitable solvent such as DMF at a suitable temperature such as 60 ° C. The protecting groups can be removed in this step to generate a compound of the formula (II), or after the reaction with a compound of the formula A-NH2 (to generate a compound of the formula (I)). Where the protecting group is 1,1-dimethylethyl carboxylate, it can be removed by treatment with trifluoroacetic acid.
Compounds of the formula (II) or salts thereof wherein R1 represents - (S02) R13 wherein R13 represents -NR11R12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached by a nitrogen atom, they can be prepared according to the following procedure: SCHEME 5 (XXI) (II; R1 = S02R13) wherein Pi, R1, R2, R3, R4, R5, R6, R7 and R8 are as defined above and L4 represents a residual group such as a halogen.
Step (xviii) comprises treatment with sulfur-hydrochloric acid. The reaction takes place at a suitable temperature such as 0 ° C.
Step (xix) comprises reaction with the corresponding amine. This reaction takes place in a suitable solvent such as DCM at a suitable temperature such as room temperature.
Step (xx) can be carried out as described above for process (b).
Step (xxi) is a step of deprotection and varies depending on the nature of Pi. Where P- \ is methyl, this step can comprise boiling with potassium hydroxide in a suitable solvent, e.g., mixture of ethanol and water.
The compounds of the formula (II) or salts thereof wherein R 1 represents - (CO) R 10 wherein R 10 represents -NR 11 R 12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and said monocyclic ring is attached to the carbonyl group by a nitrogen atom can be prepared according to the following procedure: SCHEME 6 wherein Li, Pi, R2, R3, R4, R5, R6, R7 and R8 are as defined above.
Step (xxii) can be carried out as described above for process (b).
Step (xxiii) can be carried out as described above for step (ii).
The step (xxiv) is a protection step. The nature of this reaction will depend on the protecting group. Where Pi represents methyl, this step comprises reaction with methanol, optionally in the presence of an acid (e.g., sulfuric acid).
Step (xxv) can be carried out as described above for process (a).
The step (xxvi) is a step of deprotection and varies depending on the nature of P-. Where Pi is methyl, this step comprises treating lithium hydroxide in a suitable solvent, such as a mixture of THF (tetrahydrofuran) and water, at a suitable temperature such as between room temperature and reflux.
The compounds of the formula (IV), (V), (VIII), (XV), (XVIII), (XXII) and the compounds of the formula A-NH2, (CH = CH) (CH2) rC02X, LrC02alkyl C1-3 and L3- (CH2) R10 are either commercially available or can be easily prepared from commercially available compounds using methods known to one skilled in the art.
Certain compounds of the formula (I) are also commercially available, including 5-bromo-2- (2-chlorobenzyloxy) -N- (pyridin-3-yl) benzamide, 5-chloro-2 - [(phenylmethyl) oxy] - N-3-pyridinylbenzamide, 5-bromo - / \ / -. { 3 - [(methylamino) carbonyl)] phenyl} -2 - [(phenylmethyl) oxy] benzamide and 5-chloro-2 - [(2-cyanophenyl) methoxy] -N-phenylbenzamide.
EXAMPLES The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to one skilled in the art to prepare and use the compounds, compositions, and methods of the present invention. Although particular embodiments of the present invention are described, one skilled in the art will appreciate that various changes and modifications can be made without departing from the essence and scope of the invention.
Abbreviations BINAP 2,2'-Bis (diphenylphosphino) -1, 1'-biphenyl CDI? /,? / '- Carbonyl diimidazole DCE Dichloroethane DCM Dichloromethane DEAD Diethyl Azodicarboxylate DIAD Diisopropyl Azodicarboxylate DIPEA Diisopropylethylamine DME 1, 2-Dimethoxyethane DMF N, N'-Dimethylformamide DMSO Dimethyl sulfoxide EDC / EDAC 1- (3-Dimethylaminopropyl)) - 3-ethylcarbodiimide hydrochloride HATU 0- (7-azabenzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium hexafluorophosphate HOBT 1-Hydroxybenzotriazole HPLC High Performance Liquid Chromatography KHMDS Hexamethyldisilazane Potassium MDAP Self-preparation directed to the mass Pd / C Palladium on carbon PdCI2 (dppf) 1,1'-bis (d-phenylphosphino) ferrocene-palladium dichloride (II) Pd2 (dba) 3 Tris (dibenzylidenacetone) dipalladium (0) PdOAc2 Palladium acetate Pd (PPh3) 4 Tetrakis (triphenylphosphino) palladium (0) Ph3P Triphenylphosphine SCX Strong cation exchanger Tetrakis Tetrakis (triphenylphosphino) palladium (0) THF Tetrahydrofuran TLC Thin layer chromatography TsCI 4-Toluenesulfonyl Chloride DESCRIPTION 1 2-Hydroxy-5- (1-methylethyl) benzoic acid (D1) 4-lsopropylphenol (2.7 g, 19.83 mmol) and K2CO3 (5.48 g, 39.7 mmol) were heated to 150 ° C under an atmosphere of carbon dioxide. The cooled residue was suspended in ethyl acetate and acidified with 2N hydrochloric acid. The organic layer was separated and the combined extracts were dried (MgSO4) and evaporated under reduced pressure to give the title compound which was used in the next step without further purification. 2.0 g.
MS (electrospray): m / z [M + H] + = 181 DESCRIPTION 2 Phenylmethyl 5- (1-methylethyl) -2-r (phenylmethyl) oxyflbenzoate (D2) K2CO3 (3.83 g, 27.7 mmol) was added to a stirred solution of 2-hydroxy-5- (1-methylethyl) benzoic acid (can be prepared as described in the description 1; 2.0 g, 1.10 mmol) in acetone ( 80 ml), followed by the addition of (bromomethyl) benzene (4.75 g, 27.7 mmol). The mixture was refluxed for 12 hr and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated to a yellow solid. Flash chromatography on silica gel, using 1: 10 ethyl acetate-petroleum ether gave the title compound as a 1.0 g yellow oil.
MS (electrospray): m / z [M + H] + = 361 DESCRIPTION 3 5- (1-Methylethyl) -2-f (phenylmethyl) oxy-1-benzoic acid (D3) LiOH.H20 (0.70 g, 16.65 mmol) was added to a stirred solution of phenylmethyl 5- (1-methylethyl) -2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in description 2; 1.5 g , 4.16 mmoles) in a 3: 1 mixture of THF: H20 (40 ml). The mixture was refluxed for 12 hr and then diluted with ethyl acetate (50 ml). Aqueous HCI at 10% was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4, and concentrated to give a yellow oil. 700 mg.
DESCRIPTION 4 Phenylmethyl 5-bromo-2-r (phenylmethyl) oxybenzoate (D4) Method A K2CO3 (701 mg, 5.00 mmol) was added to a stirred solution of 5-bromo-2-hydroxybenzoic acid (434 mg, 2.00 mmol) in acetone (30 mL), followed by the addition of (bromomethyl) benzene (855 mg, 5.00 mmoles). The mixture was refluxed for 12 hr and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated to a yellow solid.
Flash chromatography on silica gel, using 1: 10 ethyl acetate-petroleum ether gave the title compound as a pure, white powder. 700 mg.
MS (electrospray): m / z [M + Na] + = 419, 421 Method B Solid potassium carbonate (2.76 g, 20 mmol) was added to a solution of 5-bromo-2-hydroxybenzoic acid (1.74 g, 8 mmol) in acetone (20 mL) and the reaction mixture was stirred at 20 ° C for 20 minutes. 10 minutes. (Bromomethyl) benzene (3.42 g, 20 mmol) was added dropwise. The reaction mixture was stirred at 71 ° C for 10 hr. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to give a colorless oil. The crude product was purified on a column of silica gel, eluting with hexane: ethyl acetate (100: 5) to give the title compound as a white solid. 3 g.
MS (electroaspersion): m / z MH + = 397; [M + Na] = 419 Method C (Bromomethyl) benzene net (17.10 g, 100 mmol) was added to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (8.68 g, 40.0 mmol) and potassium carbonate (13.82 g, 100 mmol) in acetone (150 ml). ) at 20 ° C for 1 min. The reaction mixture was refluxed overnight. After filtration, the filtrate was evaporated to give the title compound as an oil which was used in the next step without further purification. 15 9 Method D (Bromomethyl) benzene (34.2 ml, 288 mmol) was added over 5 minutes to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (28.4 g, 131 mmole) and potassium carbonate (45.2 g, 327 mmole) in acetone ( 300 ml) in air at room temperature. The reaction mixture was stirred at 70 ° C overnight. After filtration, the filtrate was evaporated to give a light yellow oil, dried in a vacuum to give yellow solid, which was washed with petroleum ether (300 ml x 2), filtered and dried under vacuum to give the compound of the title as a white solid. 48.2 g.
MS (electrospray): m / z [M + H] = 397.
DESCRIPTION 5 5-bromo-2-f (phenylmethyl) oxylbenzoic acid (D5) Method A L1OH.H2O (222 mg, 5.29 mmol) was added to a stirred solution of phenylmethyl 5-bromo-2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in description 4, method A, 700 mg, 1.76 mmole) in THF (15 ml) and water (5.00 ml). The mixture was refluxed for 12 hr and then diluted with ethyl acetate (50 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO 4, and concentrated to give the title compound as a yellow solid. 400 mg.
MS (electrospray): m / z [M + H] + = 307, 309 Method B Solid LiOH (1.01 g, 42.1 mmol) was added in a single charge to a stirred solution of phenylmethyl 5-bromo-2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in description 4, method B; 3 g, 7.55 mmole) in a 3: 1 mixture of THF and water (40 ml) at 20 ° C. The reaction mixture was stirred at 71 ° C for 6 hr. After cooling to room temperature, it was diluted with ethyl acetate (200 ml). Aqueous HCI at 10% was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over Na 2 SO, and concentrated to give a white solid. The crude product was purified by silica gel chromatography eluting with hexane: ethyl acetate (3: 1) to give the title compound as a white solid. 2.1 g.
MS (electroaspersion): m / z [M + H] = 307; [M + Na] + = 329, 331 Method C Solid LiOH (5.04 g, 2.0 mmol) was added to a stirred solution of phenylmethyl 5-bromo-2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in description 4, method C, 15 g, 37.8 mmol) in THF (150 ml) and water (50.0 ml) at 20 ° C. The reaction mixture was stirred at 71 ° C overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 ml). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over Na 2 SO 4 and concentrated to give a white solid. The crude product was purified by silica gel chromatography eluting with hexane: ethyl acetate (3: 1) to give the title compound. 6.1 g.
MS (electrospray): m / z [M + Na] + = 329, 331 Method D Solid LiOH (0.53 g, 2.59 mmole) was added to a stirred solution of phenylmethyl 5-bromo-2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in the description 4; g, 2.52 mmole) in tetrahydrofuran (20 ml) and water (4.00 ml) in air at room temperature. The reaction mixture was stirred at 70 ° C overnight. After cooling to room temperature, the solvent was removed to obtain a white solid, which was dissolved in water (100 ml) and stirred in a water bath with ice. 1 N HCl (aq.) Was added to adjust the pH to 4. The white solid was filtered and dried under vacuum to give the title compound as a white solid. 0.78 g.
EM (electroaspersion): m / z [M + Na] + = 328.8 DESCRIPTION 6 5- (Methoxy) -2-f. { Phenylmethyl phenylmethyl) oxybenzoate (D6) Potassium carbonate (690 mg, 5.00 mmol) was added to a stirred solution of 2-hydroxy-5- (methyloxy) benzoic acid (336 mg, 2.00 mmol) in acetone (20 mL) followed by the addition of ((bromomethyl) Benzene (854 mg, 5.00 mmol) The mixture was refluxed for 12 hr and then cooled to room temperature, the mixture was filtered and the filtrate was concentrated to a yellow solid, flash chromatography on silica gel eluting with 1: 10 ethyl acetate: petroleum ether gave the title compound as a pure white powder 500 mg.
MS (electrospray): m / z [+ H] + = 349 DESCRIPTION 7 5- (methyloxy) -2-r (phenylmethoxy-1-benzoic acid (D7) acid) LiOH.H20 (181 mg, 4.31 mmol) was added to a stirred solution of phenylmethyl 5- (methyloxy) -2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in the description 6; 500 mg, 1 .44 mmoles) in a 3: 1 mixture of THF: H2O (40 ml). The mixture was refluxed for 12 hr and then diluted with ethyl acetate (50 ml). Aqueous HCI at 10% was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4 and concentrated to give the title as a yellow solid. 280 mg.
MS (electrospray): m / z [M + H] + = 259 DESCRIPTION 8 Phenylmethyl 5-methyl-2-f (phenylmethyl) oxobenzoate (D8) K2CO3 (1379 mg, 9.99 mmol) was added to a stirred solution of 2-hydroxy-5-methylbenzoic acid (608 mg, 4.00 mmol) in acetone (10 mL), followed by the addition of (bromomethyl) benzene (1709 mg, 9.99 mmoles). The mixture was refluxed for 12 hr and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated to a yellow solid. The crude product was purified by flash chromatography on silica gel, eluting with 1: 10 ethyl acetate-petroleum ether to give the title compound as a white powder. 1.0 g.
MS (electrospray): m / z [M + H] + = 333 DESCRIPTION 9 5-Methyl-2 - [(phenylmethyl) oxnbenzoic acid (D9) LiOH.H20 (0.379 g, 9.03 mmol) was added to a stirred solution of phenylmethyl 5-methyl-2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in the description 8; 1.0 g, 3.01 mmol) in a 3: 1 mixture of THF: H20 (40 mL). The mixture was refluxed for 12 hr and then diluted with ethyl acetate (50 ml). Aqueous HCI at 10% was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO 4 and concentrated to give the title compound as a yellow solid. 500 mg.
MS (electrospray): m / z [M + H] + = 243 DESCRIPTION 10 3,5-Dichloro ^^ iridazinamine and 5,6-dichloro-4-pyridazinamine (D10) A solution of 3,4,5-trichloropyridazine (470 mg, 2.56 mmol) in ethanol (30 mL) was cooled to 0 ° C and saturated with gaseous ammonia and stirred at room temperature for 4 days. The reaction mixture was then purged with nitrogen for 2 hr, and filtered to remove ammonium chloride. The filter cake was washed with anhydrous ethanol, the filtrate and washings were used directly in the next step.
MS (electroaspersion): m / z [M + H] + = 164, 165, 166, 167, 168, 169 DESCRIPTION 11 4-Pyridazinamine (D11) A solution of 3,5-dichloro-4-pyridazinamine and 5,6-dichloro-4-pyridazinamine (can be prepared as described in description 10; 419. 8 mg, 2.56 mmol), sodium hydroxide (246 mg, 6.14 mmol) and Pd / C (136 mg, 0.128 mmol) in ethanol (20 mL) was hydrogenated overnight. The reaction mixture was purged with nitrogen and filtered. The filtrate was concentrated to a residue and triturated with ethyl acetate. The mixture was filtered again to collect a solid which was dried to give the title compound as a yellow solid. 98 mg.
MS (electrospray): m / z [M + H] + = 96 DESCRIPTION 12 Methyl 5-cyano-2-hydroxybenzoate (D12) A suspension of methyl 5-bromo-2-hydroxybenzoate (2 g, 8.66 mmol) and copper cyanide (1861 g, 20.78 mmol) in DMF (30 mL) was stirred under nitrogen at 140 ° C for 20 hr. The reaction mixture was then cooled, quenched with water (120 ml) and extracted with ethyl acetate (3 x 80 ml). The organic phase was washed with saturated brine (50 ml), dried over sodium sulfate and evaporated under vacuum to give the title compound as a white solid. 1 g.
MS (electrospray): m / z, [M + H] + = 178 DESCRIPTION 13 Methyl 5-cyano-2-f (phenylmethyl) oxybenzoate (D13) A suspension of methyl 5-cyano-2-hydroxybenzoate (can be prepared as described in the description 12; 531 mg, 3 mmol), potassium carbonate (1037 mg, 7.50 mmol) and (bromomethyl) benzene (1026 mg, 6.00 mmol) in acetone (60 ml) was stirred at 50 ° C overnight. The mixture was cooled and filtered. The filtrate was concentrated. The crude product was purified by silica gel chromatography eluting with hexane: ethyl acetate (10: 1) to give the title compound as a white solid. 480 mg.
MS (electrospray): m / z, [M + H] + = 268 DESCRIPTION 14 5-Cyano-2-f (phenylmethyl) oxy-1-benzoic acid (D14) To a stirred solution of methyl 5-cyano-2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in 13, 200 mg, 0.75 mmol) in THF (2 mL) was added a hydroxide solution of lithium (94 mg, 2.25 mmol) in water (8 ml). The reaction mixture was stirred at room temperature overnight. The THF was removed and the mixture was adjusted to pH 7 with 2N HCl. The mixture was filtered and the residue was dried to give the title compound as a yellow solid. 160 mg.
MS (electrospray): m / z, [M + H] + = 254 DESCRIPTION 15 5-Bromo-2- (f (4-chlorophenyl) methyloxy> (4-chlorophenyl) methyl benzoate (D15) 1- (Bromomethyl) -4-chlorobenzene (592 mg, 2.88 mmol) was added in a single charge to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (250 mg, 1.15 mmol) and potassium carbonate (478 mg, 3.46 mmole) in acetone (40 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at 55 ° C for 18 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (30 x 3 ml) and evaporated under vacuum to give the title compound as an off-white solid. 320 mg.
MS (electrospray): m / z [M + Na] + = 487, 489, 491 DESCRIPTION 16 5-bromo-2- (r (4-chlorophenyl) methyloxy) benzoic acid (D16) A solution of lithium hydroxide (64 mg, 6.86 mmol) in water (20.00 ml) was added dropwise to a stirred solution of 5-bromo-2-. { [(4-chlorophenyl) methyl] oxy} (4-chlorophenyl) methyl benzoate (can be prepared as described in the description 15; 320 mg, 0.69 mmol) in THF (20 mL) for 5 min. The reaction mixture was then stirred at 20 ° C for 16 hr. The organic phase was evaporated and the residual aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 mL) was adjusted to pH 2 with 2M hydrochloric acid (1 mL) and extracted with ethyl acetate (3 x 20 mL). The organic phase was evaporated under vacuum to give the title compound as a light yellow solid. 180 mg.
MS (electroaspersion): m / z [M + Na] + = 363, 365, 367 DESCRIPTION 17 5-Bromo-2 - ((4- (methyloxy) phenylmethyl) oxy) benzoate of G4- (methyloxy) phenylmethyl (D7) 1- (Bromomethyl) -4-methoxybenzene (510 mg, 2.53 mmol) was added in a single charge to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (250 mg, 1.15 mmol) and potassium carbonate (318 mg, 2.30 mmol) in acetone (40 ml) for 1 min under nitrogen. The reaction mixture was stirred at 55 ° C for 16 hr. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (3 x 30 ml) and evaporated under vacuum to give the title compound as a light yellow solid. 400 mg.
MS (electrospray): m / z [M + Na] + = 479, 481 DESCRIPTION D18 5-bromo-2 - ((f4- (methoxy) phenanthyl) oxy) benzoic acid (D18) A solution of lithium hydroxide (367 mg, 8.75 mmol) in water (20 mL) was added dropwise to a stirred solution of 5-bromo-2- ( { [4- (methyloxy) phenyl] methyl. oxi) benzoate of [4- (methyloxy) pheny] methyl (can be prepared as described in the description 17; 400 mg, 0.875 mmole) in THF for 1 min. The reaction mixture was stirred at 20 ° C for 6 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 mL) was adjusted to pH 2 with 2M hydrochloric acid (1 mL) and extracted with ethyl acetate (3 x 20 mL). The organic phase was evaporated under vacuum to give the title compound as a light yellow solid. 200 mg.
MS (electrospray): m / z [+ Na] + = 359, 361 DESCRIPTION 19 5-Fluoro-2-f (phenylmethyl) oxy-phenylmethylbenzoate (D19) A suspension of 5-fluoro-2-hydroxybenzoic acid (468 mg, 3 mmol), potassium carbonate (1037 mg, 7.50 mmol) and (bromomethyl) benzene (1283 mg, 7.50 mmol) in acetone (60 ml) was stirred at 50 ° C at night. The mixture was cooled and filtered. The filtrate was concentrated and the crude product was purified by silica gel chromatography, eluting with hexane: ethyl acetate (10: 1) to give the title compound as a colorless oil. 860 mg.
MS (electrospray): m / z [M + Na] + = 359 DESCRIPTION 20 5-Fluoro-2 - [(phenylmethyl) oxy] benzoic acid (D20) A solution of lithium hydroxide (71.9 mg, 3.00 mmol) in water (12 ml) was added to a stirred solution of phenylmethyl 5-fluoro-2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in Description 19, 336 mg, 1 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature overnight. The THF was removed, the mixture adjusted to pH 7 with 2N HCl. The mixture was filtered and the residue was dried to give the title compound as a white solid. 180 mg.
MS (electrospray): m / z [M + Na] + = 269 DESCRIPTION 21 5-Bromo-2-. { (3-chlorophenyl) methyl (3-chlorophenyl) methynoxy) benzoate (D21) 3-Chlorobenzyl bromide (568 mg, 2.76 mmol) was added dropwise to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (200 mg, 0.92 mmol) and potassium carbonate (255 mg, 1.84 mmol) in acetone (40 mi) for 1 min. The reaction mixture was stirred at 56 ° C for 24 hr. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (3 x 30 ml) and evaporated under vacuum to give the title compound as an off-white solid. 427 mg.
MS (electrospray): m / z [M + Hf = 465, 467, 469, 471 DESCRIPTION 22 5-bromo-2 - ([(3-chlorophenyl) methyloxy) benzoic acid (D22) A solution of lithium hydroxide (384 mg, 9.16 mmol) in water (20 ml) was added dropwise to a stirred solution of 5-bromo-2-. { [(3-chlorophenyl) methyl] oxy} (3-chlorophenyl) methyl benzoate (can be prepared as described in the description 21; 427 mg, 0.92 mmol) in THF (20 mL) for 1 min. The reaction mixture was stirred at 20 ° C for 16 hr. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3 x 20 mL). The organic phase was evaporated under vacuum to give the title compound as a white solid. 200 mg.
MS (electroaspersion): m / z [M + Na] + = 363, 365, 367 DESCRIPTION 23 5-Bromo-2-. { [(4-cyanophenyl) methyloxy] > (4-cyanophenyl) methyl benzoate (D23) 4- (Bromomethyl) benzonitrile (318 mg, 1622 mmol) was added in a single charge to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (160 mg, 0.74 mmol) and potassium carbonate (204 mg, 1.48). mmoles) in acetone (40 ml) at 20 ° C. The reaction mixture was stirred at 55 ° C for 18 h. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (3 x 30 ml) and evaporated under vacuum to give the title compound as an off-white solid. 300 mg.
MS (electrospray): m / z [M + H] + = 447, 449; [M + Na] + = 469, 471 DESCRIPTION 24 5-Bromo-2- (f (4-cyanophenyl) methoxy> benzoic acid (D24) Lithium hydroxide (281 mg, 6.71 mmol) in water (20 ml) was added dropwise to a stirred solution of 5-bromo-2-. { [(4-cyanophenyl) methyl] oxy} (4-cyanophenyl) methyl benzoate (can be prepared as described in the description 23; 300 mg, 0.67 mmol) in THF (20 mL) for 5 min. The reaction mixture was stirred at 20 ° C for 16 hr. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3 x 20 mL). The organic phase was then evaporated under vacuum to give the title compound as a light yellow solid. 145 mg.
MS (electroaspersion): m / z [M + H] + = 332, 334; [M + Na] + = 354, 356 DESCRIPTION 25 5-Bromo-2-. { (3-cyanophenyl) methyl (3-cyanophenyl) methyl-1-yl) benzoate (D25) 3-Cyanobenzyl bromide (542 mg, 2.76 mmol) was added dropwise to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (200 mg, 0.92 mmole) and potassium carbonate (255 mg, 1.84 mmole) in acetone (40 mi) for 1 min. The reaction mixture was then stirred at 56 ° C for 24 hr. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (100 ml) and evaporated under vacuum to give the title compound as an off-white solid. 41 mg.
DESCRIPTION 26 5-bromo-2- (r (3-cyanophenyl) methyloxy) benzoic acid (D26) A solution of lithium hydroxide (386 mg, 9.19 mmol) in water (20.00 ml) was added dropwise to a stirred solution of 5-bromo-2-. { [(3-cyanophenyl) methyl] oxy} (3-cyanophenyl) methyl benzoate (can be prepared as described in the description 25; 41 1 mg, 0.92 mmol) in THF (20 mL) for 1 min. The reaction mixture was stirred at 20 ° C for 16 hr. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3 x 20 mL). The organic phase was evaporated under vacuum to give the title compound as an off-white solid. 200 mg.
MS (electrospray): m / z [M + H] DESCRIPTION 27 (2-Chlorophenyl) methyl 5-Bromo-2- (2-chlorophenyl) methyloxy) benzoate (D27) 1- (Bromomethyl) -2-chlorobenzene (833 mg, 4.05 mmol) was added dropwise to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (400 mg, 1.84 mmol) and potassium carbonate (509 mg, 3 mg). , 69 mmol) in acetone (50 ml) for 1 min under nitrogen. The reaction mixture was stirred at 55 ° C for 16 hr. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (3 x 30 ml) and evaporated under vacuum to give the title compound as a light yellow solid. 520 mg.
MS (electrospray): m / z [M + Na] + = 487, 489, 491, 493 DESCRIPTION 28 5-bromo-2- acid. { r (2-chlorophenyl) methyloxy} benzoic (D28) A solution of lithium hydroxide (468 mg, 1.16 mmol) in water (25 m) was added dropwise to a stirred solution of 5-bromo-2-. { [(2-chlorophenyl) methyl] oxy} (2-chlorophenyl) methyl benzoate (can be prepared as described in the description 27; 520 mg, 1.12 mmol) in THF (25 mL) for 1 min. The reaction mixture was stirred at 20 ° C for 16 hours. The organic phase was evaporated and the aqueous phase (25 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml) and extracted with ethyl acetate (3 x 20 ml). The organic phase was evaporated under vacuum to give the title compound as a light yellow solid. 350 mg.
MS (electrospray): m / z [M + H] + = 341, 343 DESCRIPTION 29 5-Bromo-2- (3- (methyloxy) phennmethyl) oxy) benzoate of G3- (methyloxy) phenylmethyl (D29) 1- (Bromomethyl) -3-methoxybenzene net (510 mg, 2.53 mmol) was added in one charge to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (250 mg, 1.15 mmol) and potassium carbonate (318 mg, 2.304 mmole) in acetone (40 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at 55 ° C for 16 hr. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (3 x 30 ml) and evaporated under vacuum to give the title compound as an off-white solid. 430 mg.
MS (electrospray): m / z [M + Na] + = 479, 481 DESCRIPTION 30 5-Bromo-2- ( { F3- (methyloxy) phenyl) methyl acid > oxy) benzoic (D30) A solution of lithium hydroxide (395 mg, 9.40 mmol) in water (20 mL) was added dropwise to a stirred solution of 5-bromo-2- ( { [3- (methyloxy) phenyl] methyl. oxi) [3- (methyloxy) phenyl] methyl benzoate (can be prepared as described in the description 29; 430 mg, 0.94 mmol) in THF (20 mL) for 1 min. The reaction mixture was stirred at 20 ° C for 16 hr. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3 x 20 mL). The organic phase was evaporated under vacuum to give the title compound as a light yellow solid. 275 mg.
MS (electrospray): m / z [M + Naf = 359, 361 DESCRIPTION 31 5-Bromo-2- ( { F2- (methyloxy) phenylmethyl) oxy) benzoate of G2- (methyloxy) pheninmethyl (D31) 1- (Chloromethyl) -2-methoxybenzene net (397 mg, 2.53 mmol) was added in a charge to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (250 mg, 1.15 mmol) and cesium carbonate (751 mg, 2.30 mmol) in acetone (40 ml) under nitrogen at 20 ° C. The reaction mixture is stirred at 55 ° C for 16 hr. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (3 x 30 ml) and evaporated under vacuum to give the title compound as a light yellow liquid. 420 mg.
MS (electrospray): m / z [M + Na] + = 479, 481 DESCRIPTION 32 5-bromo-2 - ((f2- (methyloxy) phenanthyl) oxy) benzoic acid (D32) A solution of lithium hydroxide (385 mg, 9.18 mmol) in water (20 mL) was added dropwise to a stirred solution of 5-bromo-2- ( { [2- (methyloxy) phenyl] methyl. oxi) benzoate of [2- (methyloxy) phenyl] methyl (can be prepared as described in the description 31; 420 mg, 0.92 mmol) in THF (20 ml) for 5 min. The reaction mixture was stirred at 20 ° C for 16 hr. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The aqueous phase was then extracted with ethyl acetate (3 x 20 mL). The organic phase was then evaporated under vacuum to give the title compound as a light yellow solid. 280 mg.
MS (electrospray): m / z [M + Na] + = 359, 361 DESCRIPTION 33 5-Bromo-2- (r (2-cyanophenyl) methyl-oxy) benzoate (2-cyanophenyl) methyl (D33) 2- (Bromomethoxy) benzonitrile (397 mg, 2027 mmol) was added in a charge to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (200 mg, 0.92 mmol) and potassium carbonate (255 mg, 184 mmol). ) in acetone (40 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at 55 ° C for 16 hr. The organic phase was evaporated and the residue was washed with water (25 ml), extracted with ethyl acetate (100 ml) and evaporated under vacuum to give the title compound as an off-white solid. 350 mg.
MS (electrospray): m / z [M + H] + = 447, 449; [M + Na] + = 469, 471 DESCRIPTION 34 5-Bromo-2- (r (2-cyanophenyl) methyloxy] benzoic acid (D34) A solution of lithium hydroxide (328 mg, 7.83 mmol) in water (20 m) was added dropwise to a stirred solution of 5-bromo-2-. { [(2-cyanophenyl) methyl] oxy} (2-cyanophenyl) methyl benzoate (can be prepared as described in the description 34; 350 mg, 0.78 mmol) in THF (20 mL) for 1 min. The reaction mixture was stirred at 20 ° C for 8 hr. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml). The residual water phase was extracted with ethyl acetate (3 x 20 mL). The organic phase was then evaporated under vacuum to give the title compound as a light yellow solid. 160 mg.
MS (electrospray): m / z [M + H] + = 332, 334 DESCRIPTION 35 5-Bromo-2-hydroxy-N-3-pyridinylbenzamide (D35) A solution of 5-bromo-2-hydroxybenzoic acid (5.2 g, 23.96 mmoles), 3-pyridinamine (2.26 g, 23.96 mmoles), EDC (4.59 g, 23.96 mmoles), HOBT (3.67 g, 23.96 mmoles) and triethylamine ( 3.34 mL, 23.96 mmol) in DMF (80 mL) was stirred for 3 hr. The reaction mixture was filtered. 150 ml of water was added to the filtrate to give a white solid. This was filtered and dried to give the title compound. 2.8 g.
MS (electrospray): m / z [M + H] + = 293, 295 DESCRIPTION 36 2-Hydroxy-5- (r (4-methylphenyl) sulfonanoxy) methyl benzoate (D36) A mixture of methyl 2,5-dihydroxybenzoate (1.5 g, 8.92 mmol), potassium carbonate (7.50 g, 54.2 mmol), and dry acetone (100 mL) was stirred at room temperature for 30 min. To the mixture was added TsCI (1.72 g, 9.00 mmol) in portions and the mixture was refluxed for hr. The reaction mixture was used in the next step directly.
MS (electrospray): m / z [M + H] + = 323 DESCRIPTION 37 5- (methyl r (4-methylphenyl) sulfonyl-oxoxy-2-f (phenylmethyl) oxy-benzoate (D37) Method A (Bromomethyl) benzene (3.81 g, 22.26 mmole) was added to 2-hydroxy-5-. { [(4-methylphenyl) sulfonyl] oxy} Methyl benzoate (can be prepared as described in description 36; 2.87 g, 8.90 mmol) and the resulting mixture refluxed overnight. After cooling, the resulting precipitate was filtered and the filtrate was evaporated. The crude product was purified by silica gel chromatography, eluting with a 4: 1 mixture of hexane: ethyl acetate to give the title compound as a colorless oil. 2.7 g.
MS (electrospray): m / z, [M + H] + = 413 Method B A mixture of methyl 2,5-dihydroxybenzoate (2.5 g, 14.87 mmol), potassium carbonate (25 g, 181 mmol), and dry acetone (50 mL) was stirred at room temperature for 30 min. 4-Methylbenzenesulfonyl chloride (2.86 g, 15.00 mmol) was added in portions and the mixture was refluxed for 7 hr. (Bromomethyl) benzene (6.35 g, 37.2 mmoles) was added and the resulting mixture was refluxed overnight. After cooling, the precipitate was filtered and the filtrate was evaporated. The residue was loaded on a column of silica gel, and eluted with petroleum ether: ethyl acetate = 4: 1 to give the title compound as a white solid. 2.6 g.
MS (electrospray): m / z [M + H] + = 413.0.
Method C A mixture of methyl 2,5-dihydroxybenzoate (10 g, 59.5 mmol), potassium carbonate (50.0 g, 362 mmol), and dry acetone (450 mL) was stirred at room temperature for 30 min. 4-Methylbenzenesulfonyl chloride (1.44 g, 60.0 mmol) was added in portions and the mixture was refluxed for 7 hr. (Bromomethyl) benzene (25.4 g, 149 mmol) was added and the resulting mixture was refluxed overnight. After cooling, the precipitate was filtered and the filtrate was evaporated. The residue was loaded on a column of silica gel and eluted with hexane / ethyl acetate = 4: 1 to give the title compound as a yellow solid. 22 g.
MS (electrospray): m / z [M + H] + = 413 DESCRIPTION 38 5-Hydroxy-2-f (phenylmethyl) oxylbenzoic acid (D38) Method A 5-. { [(4-Methylphenyl) sulfonyl] oxy} -2 - [(Phenylmethyl) oxy] benzoate methyl (can be prepared as described in description 37; 2.5 g, 6.06 mmol) was boiled with potassium hydroxide (2.38 g, 42.4 mmol) in a mixture of ethanol (60 ml) and water (15 ml) for 4 hours. hr. After the ethanol was evaporated, the aqueous solution was washed with ethyl acetate (20 mL) and acidified with concentrated HCl. The mixture was extracted with ethyl acetate (3 x 30 mL). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate and evaporated under vacuum to give the title compound as a yellow oil. 1.35 g.
MS (electroaspersion): m / z [M + H] + = 245; [M + Na] + = 267 Method B 5-. { [(4-Methylphenyl) sulfonyl] oxy} Methyl -2- [(phenylmethyl) oxy] benzoate (can be prepared as described in the description 75; 9.0 g, 21 .82 mmole) was boiled with potassium hydroxide (8.57 g, 153 mmol) in a mixture of ethanol (160 ml) and water (40 ml) for 3 hr. After the ethanol was evaporated, the aqueous solution was washed with ethyl acetate (250 ml), and then acidified with concentrated HCl. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over Na 2 SO 4 and evaporated under vacuum to give the title compound as a yellow oil. 5.2 g.
MS (electrospray): m / z [M + H] + = 244.9.
Method C 5-. { [(4-Methylphenyl) sulfonyl] oxy} Methyl-2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in the description 75; 22.0 g, 53.3 mmol) was boiled with potassium hydroxide (20.95 g, 373 mmol) in a mixture of ethanol (320 mi) and water (80 mi) during the night. After the ethanol was evaporated, the aqueous solution was washed with ethyl acetate (500 ml), and then acidified with concentrated HCl. The mixture was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over sodium sulfate and evaporated under vacuum to give the title compound as a yellow oil. 14 g.
MS (electrospray): m / z [MH + 23] + = 267 DESCRIPTION 39 5- (4-Methyl-1-piperazinyl) -2-f. { phenylmethyl phenylmethyl) oxybenzoate (D39) Cesium carbonate (574 mg, 1.76 mmol) was finely ground in a glove box filled with nitrogen and weighed in a kiln-dried Schlenk flask. The flask was quickly capped with a rubber stopper and purged with argon. Pd2 (dba) 3 (2.88 mg, 3.15 pmol) and BINAP (5.88 mg, 9.44 μ) were added to the flask, followed by benzyl 2- (benzyloxy) -5-bromobenzoate (can be prepared as follows). describes in the description 4, 500 mg, 1.26 mmol), 1-methylpiperazine (126 mg, 126 mmol), and toluene (10 ml). The solution was refluxed for 10 hr. The solution was then cooled to room temperature, diluted with ether, filtered and concentrated under vacuum to give the title compound which was not further purified 100 mg.
MS (electrospray): m / z [M + H] + = 417 DESCRIPTION 40 5- (4-Methyl-1-piperazinyl) -2-f (phenylmethyloxybenzoic acid (D40) acid) Lithium hydroxide (17.25 mg, 0.72 mmol) was added to a stirred solution of phenylmethyl 5- (4-methyl-1-piperazinyl) -2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in the description 39; 100 mg, 0.24 mmol) in a THF.water mixture (3: 1, 10 ml). The mixture was refluxed for 12 hr and then diluted with ethyl acetate (50 ml). Aqueous HCI at 10% was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over magnesium sulfate and concentrated to give a white solid. The product was purified using Comflash to give the title compound. 50 mg.
MS (electrospray): m / z [M + H] + = 327 DESCRIPTION 41 2-r (Phenylmethyl) oxn-5- (1-piperidinyl) benzoate of phenylmethyl (D41) Cesium carbonate (689 mg, 2.1 1 mmol) was ground finely in a glove box filled with nitrogen and weighed in a homogenized Schlenk flask. The flask was quickly capped with a rubber stopper and purged with argon. Pd2 (dba) 3 (3.46 mg, 3.78 pmol) and BINAP (7.05 mg, 0.01 mmol) were added to the flask, followed by benzyl 2- (benzyloxy) -5-bromobenzoate (can be prepared as described in the description) 4, 600 mg, 151 mmol), piperidine (129 mg, 1510 mmol), and toluene (10 mL). The solution was refluxed for 10 hr. The solution was then cooled to room temperature, diluted with ether, filtered and concentrated in vacuo to give the title compound.
MS (electrospray): m / z [M + H] + = 402 DESCRIPTION 42 2-r (phenylmethyl) oxy1-5- (1-pyridinyl) benzoic acid (D42) LiOH (125 mL, 3.74 mmol) was added to a stirred solution of phenylmethyl 2 - [(phenylmethyl) oxy] -5- (1-piperidinyl) benzoate (can be prepared as described in description 41; 150 mg, 0.37. mmoles) in a THF: water mixture (3: 1, 10 ml). The mixture was refluxed for 12 hr and then diluted with ethyl acetate (50 ml). Aqueous HCI at 10% was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over magnesium sulfate, and concentrated to give a yellow oil. The crude product was purified using Comflash to give the title compound. 80 mg.
DESCRIPTION 43 Phenylmethyl 5-chloro-2 - [(phenylmethyl) oxobenzoate (D43) A mixture of 5-chloro-2-hydroxybenzoic acid (2.03 g, 1.8 mmol), benzyl bromide (2.79 mL, 23.5 mmol) and potassium carbonate (4.87 g, 35.3 mmol) in DMF (20 mL) was stirred at room temperature overnight, then heated at 60 ° C for 1 hour. It was cooled, diluted with water (50 ml) and extracted with ethyl acetate (x3). The organics were washed with water (x2) and brine, dried (MgSO4), and concentrated in vacuo to give the crude title compound as a yellow oil which was used immediately without further purification.
DESCRIPTION 44 (3-Aminophenyl) methyl acetate (D44) A mixture of (3-aminophenyl) acetic acid (5.0 g, 33 mmol), methanol (50 mL), and C.H2SO4 (10 mL) was heated to reflux overnight. The solvent was evaporated under vacuum and the residue was taken up in water (50 ml) and ethyl acetate (200 ml). Solid Na 2 CO 3 was added until the solution was pH 10. The layers were separated and the aqueous layer was extracted again with ethyl acetate (250 ml). The organic layers were combined, washed with brine, dried (MgSO 4) and evaporated under vacuum to give the title compound as a brown oil. 5.0 g.
MS (electrospray): m / z [M + H] + = 166 DESCRIPTION 45 5-chloro-2-f (phenylmethyl) oxnbenzoic acid (D45) Phenylmethyl 5-chloro-2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in description 43; 4.16 g, 1.8 mmol), in ethanol (40 ml) and NaOH 2 (20 ml) was heated at reflux for two hours. The mixture was cooled, concentrated in vacuo, acidified with 2M HCl and extracted with ethyl acetate (x3). The organic compounds were washed with brine, dried (MgSO 4), and concentrated to give a yellow oil. Purified using Biotage chromatography (Cartridge C18, CH3CN / H20) to give the title compound as a white solid. 1.9 g.
MS (electrospray): m / z [M + Na] + = 285, 287 DESCRIPTION 46 (3-f ((5-Chloro-2 - [(phenylmethyl) oxyphenyl> methyl / amino-1,5-phenyl) methyl acetate (D46) A mixture of 5-chloro-2- [. { phenylmethyl) oxy] benzoic acid (can be prepared as described in the description 45, 50 mg, 0.19 mmol), methyl (3-aminophenyl) acetate (can be prepared as described in the description 44, 48 mg, 0.29 mmol) , EDAC (56 mg, 0.29 mmol), and dichloromethane (3 mL) was heated in the microwave at 60 ° C for 40 minutes. DIPEA (53 μ ?, 0.3 mmol) was added and the mixture was heated at 60 ° C in the microwave for another 20 minutes. The reaction mixture was purified by SCX cartridge, eluting with methanol. The fractions were combined and evaporated to give the title compound as an off-white solid. 35 mg.
MS (electrospray): m / z [M + H] + = 410, 412 DESCRIPTION 47 4-r (phenylmethyl) oxy-1, 3-benzenedicarboxylate of Bis (phenylmethyl) (D47) To a suspension of 4-hydroxy-1,3-benzenedicarboxylic acid (5 g, 27.5 mmol) and K2CO3 (3.66 g, 99 mmol) in acetone (80 ml) stirred at room temperature was added (bromomethyl) benzene (16.90 g, 99 mmol) drop by drop. The reaction mixture was stirred at 50 ° C overnight. The mixture was cooled to room temperature and filtered. The filtrate was concentrated to give the crude product, which was added to a column of silica gel (100 g) and eluted with hexanes / ethyl acetate = 10: 1 (2 L) to give the title compound as an oil colorless. 6.6 g.
MS (electrospray): m / z [M + Na] + = 474.9 DESCRIPTION 48 4 - [(Phenylmethyl) oxn-l3-benzenedicarboxylic acid (D48) A solution of LiOH (6.12 g, 146 mmol) in water (100 ml) was added to a stirred solution of bis (phenylmethyl) 4 - [(phenylmethyl) oxy] -1,3-benzenedicarboxylate (can be prepared as described in the description 47; 6.6 g, 14.59 mmoles) in tetrahydrofuran (25 ml) at room temperature. The mixture was stirred at room temperature overnight. The reaction mixture was acidified with concentrated HCl. The white precipitate was collected by filtration and dried to give the title compound as a white solid. 3 8 g.
MS (electrospray): m / z [M + Na] + = 294.9 DESCRIPTION 49 3-r (methyloxy) carbonin-4-r (phenylmethyl) oxy-benzoic acid (D49) H2SO4 (0.8 mL, 1.02 mmol) was added dropwise to a solution of 4- [. { phenylmethyl) oxy] -1,3-benzenedicarboxylic acid (it can be prepared as described in the description 48; 3 g, 11.02 mmol) in methanol (40 ml). The mixture was stirred at room temperature for 3 hr before being purged in ice water (40 ml). The precipitate was collected and added to a saturated NaHCO 3 solution. The mixture was filtered to remove the insoluble residue and the pH of the filtrate was adjusted to pH = 4.8 by HCl (6 mol / L). The precipitate was collected to give crude product. The crude product was added to a column of silica gel (300 g), and eluted with dichloromethane / methanol = 100: 1 (3 L) to give a mixture of 5 - [(methyloxy) carbonyl] -2- [ (phenylmethyl) oxy] benzoic acid and the title compound as a white solid. 1 g.
MS (electrospray): m / z [M + Na] + = 309.0 DESCRIPTION 50 5 - [(4-Methyl-1-piperazinyl) carbon] n-2-methyl f (phenylmethyl) oxybenzoate (D50) Oxalyl chloride (0.46 mL, 5.24 mmol) was added dropwise to a stirred solution of 3 - [(methyloxy) carbonyl] -4 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 49 300 mg, 1.05 mmoles) in dichloromethane (10 ml) and dimethyl formamide (3 drops) at room temperature. The mixture was stirred at room temperature for 1 hr, and then concentrated to dryness. The residue was dissolved in dichloromethane (5 ml), and then added to a solution of 1-methylpiperazine (525 mg, 5.24 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 2 hr. Water (60 mL) was added and the mixture was extracted with dichloromethane (3 x 60 mL). The organic phase was washed with saturated brine (50 ml), dried over sodium sulfate and evaporated under vacuum to give crude product. The crude product was added to a column of silica gel and eluted with dichloromethane / methanol = 0: 1 to give the title compound as a colorless oil. 345 mg.
EM (electrospray): m / z [M + H] + = 369.1 DESCRIPTION 51 5-R (4-methyl-1-piperazinyl) carbonill-2-f (phenylmethyl) oxy-1-benzoic acid (D51) A solution of LiOH (393 mg, 9.36 mmol) in water (10 mL) was added to a stirred solution of methyl 5 - [(4-methyl-1-piperazinyl) carbonyl] -2 - [(phenylmethyl) oxy] benzoate. (can be prepared as described in the description 50; 345 mg, 0.94 mmol) in tetrahydrofuran (2.5 ml) at room temperature. The mixture was stirred at room temperature for 3 hr. The mixture was acidified with HCl (6 mol / L). The solvent was evaporated under vacuum to give the crude product. The crude product was used directly in the next step without further purification.
MS (electrospray): m / z [M + H] + = 355.0 DESCRIPTION 52 2 - [(Phenylmethyl) oxy-1-5- (1-piperidinylcarbonyl) benzoate methyl (D52) Oxalyl chloride (0.61 ml, 6.99 mmol) was added dropwise to a stirred solution of 3 - [(methyloxy) carbonyl] -4 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 49 400 mg, 1.40 mmol) in dichloromethane (10 ml) and dimethylformamide (3 drops) at room temperature. The mixture was stirred at room temperature for 1 hr. The solvent was then removed and the residue was dissolved in dichloromethane (5 ml). This mixture was added to a solution of 1-methylpiperazine (525 mg, 5.24 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 2 hr. Water (60 ml) was added to the mixture, which was then extracted with dichloromethane (3 x 60 ml). The organic phase was washed with saturated brine (50 ml), dried over sodium sulfate and evaporated under vacuum to give the crude product. The crude product was loaded on a column of silica gel (200 g) and eluted with dichloromethane / methanol = 50: 1 to give the title compound as a colorless oil. 450 mg.
MS (electrospray): m / z [M + H] + = 354 DESCRIPTION 53 2-f (phenylmethyl) oxn-5- (1-piperidinylcarbonyl) benzoic acid (D53) A solution of LiOH (534 mg, 12.73 mmol) in water (8 ml) was added to a stirred solution of methyl 2 - [(phenylmethyl) oxy] -5- (1-piperidinylcarbonyl) benzoate (can be prepared as described in the description 52; 450 mg, 1.27 mmoles) in tetrahydrofuran (2 ml) at room temperature. The mixture was stirred at room temperature for 3 hr. The mixture was then acidified with 6N HCl and the precipitate was collected and dried to give the title compound as a white solid. 400 mg.
MS (electrospray): m / z [M + H] + = 340 DESCRIPTION 54 Methyl 2-f (phenylmethyl) oxyl-5- (1-pyrrolidinylcarbonyl) benzoate (D54) Oxalyl chloride (0.61 ml, 6.99 mmol) was added dropwise to a stirred solution of 3 - [(methyloxy) carbonyl] -4 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 49 400 mg, 1.40 mmol) in dichloromethane (10 ml) and dimethylformamide (3 drops) at room temperature. The mixture was stirred at room temperature for 1 hr. The solvent was removed, and the residue was dissolved in dichloromethane (5 ml). This mixture was added to a solution of pyrrolidine (497 mg, 6.99 mmol) in dichloromethane (5 ml) and the mixture was stirred at room temperature for 2 hours. hr. Water (60 mL) was added and the mixture was extracted with dichloromethane (3 x 60 mL). The organic phase was washed with saturated brine (50 ml), dried over sodium sulfate and evaporated under vacuum to give the crude product. The crude product was loaded on a column of silica gel (200 g), and eluted with dichloromethane / methanol = 50: 1 to give the title compound as a colorless oil. 400 mg.
MS (electrospray): m / z [M + H] + = 340 DESCRIPTION 55 2 - [(Phenylmethyl) oxy1-5- (1-pyrrolidinylcarbonylbenzoic acid (D55)] A solution of LiOH (495 mg, 1.79 mmoles) in water (8 ml) was added to a stirred solution of methyl 2 - [(phenylmethyl) oxy] -5- (1-pyrrolidinylcarbonyl) benzoate (can be prepared as follows). described in the description 54; 400 mg, 1.18 mmol) in tetrahydrofuran (2 ml) at room temperature. The mixture was stirred at room temperature for 3 hr. The mixture was acidified with HCl (6 mol / l). The precipitate was collected and dried to give the title compound as a white solid. 300 mg.
MS (electrospray): m / z [M + H] + = 326 DESCRIPTION 56 5- (4- orpholinylcarbonyl) -2-methyl f (phenylmethyl) oxobenzoate (D56) Oxalyl chloride (0.61 ml, 6.99 mmol) was added dropwise to a stirred solution of 3 - [(methyloxy) carbonyl] -4 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in the description 49; 400 mg, 1.40 mmol) in dichloromethane (10 ml) and dimethylformamide (3 drops) at room temperature. The mixture was stirred at room temperature for 1 hr. The solvent was removed. The residue was dissolved in dichloromethane (5 ml). This mixture was added to a solution of morpholine (609 mg, 6.99 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 2 hr. Water (60 mL) was added and the mixture was extracted with dichloromethane (3 x 60 mL). The organic phase was washed with saturated brine (50 ml), dried over sodium sulfate and evaporated under vacuum to give the crude product as a colorless oil. The crude product was loaded on a column of silica gel and eluted with dichloromethane / methanol = 20: 1 to give the title compound as a colorless oil. 450 mg.
MS (electrospray): m / z [M + H] + = 356 DESCRIPTION 57 5- (4-Morpholinylcarbonyl) -2-f (phenylmethyl) oxy-1-benzoic acid (D57) A solution of LiOH (420 mg, 10 mmol) in water (8 ml) was added to a stirred solution of methyl 5- (4-morpholinylcarbonyl) -2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in the description 56, 450 mg, 1.27 mmoles) in tetrahydrofuran (2 ml) at room temperature. The mixture was stirred at room temperature for 3 hr. The mixture was acidified with HCl (6 mol / l), extracted with ethyl acetate (3 x 40 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate and evaporated under vacuum to give crude title compound as a white solid. 400 mg.
MS (electrospray): m / z [M + H] + = 342 DESCRIPTION 58 Methyl 5-f (dimethylamino) carbonyl1-2-f (phenylmethyl) oxylbenzoate (D58) Oxalyl chloride (0.46 mL, 5.24 mmol) was added dropwise to a stirred solution of 3 - [(methyloxy) carbonyl] -4 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 49 300 mg, 1.05 mmol) in dichloromethane (10 ml) and dimethylformamide (3 drops) at room temperature. The mixture was stirred at room temperature for 1 hr. The solvent was removed and the residue was dissolved in dichloromethane (5 ml). This The mixture was added to a solution of dimethylamine (716 mg, 5.24 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 2 hr. Water (40 ml) was added and the mixture was extracted with dichloromethane (3 x 60 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate and evaporated under vacuum to give the crude product as a colorless oil. The crude product was used directly in the next step without further purification.
MS (electrospray): m / z [M + H] + = 314 DESCRIPTION 59 5 (Dimethylamino) carbonin-2-f (phenylmethyl) oxnbenzoic acid (D59) A solution of LiOH (585 mg, 13.95 mmol) in water (8 ml) was added to a stirred solution of methyl 5 - [(dimethylamino) carbonyl] -2 - [(phenylmethyl) oxy] benzoate (can be prepared as follows). described in the description 58, 437 mg, 1.40 mmol) in tetrahydrofuran (2 ml) at room temperature. The mixture was stirred at room temperature for 3 hr. The mixture was acidified with HCl (6 mol / L) and extracted with ethyl acetate (3 x 40 mL). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate and evaporated under vacuum to give the crude product as a white solid. 350 mg.
MS (electrospray): m / z [M + H] + = 300 DESCRIPTION 60 5- (Chlorosulfonyl) -2-hydroxybenzoate methyl (D60) Sulfurochlorhydric acid (38.3 g, 329 mmol) at 0 ° C was added to methyl 2-hydroxybenzoate (10 g, 65.7 mmol) in small portions and the mixture was then stirred at 0 ° C for 1 hr. The mixture was added dropwise to 10 ml of ice water with stirring and stirring was continued for an additional 0.5 hr. The resultant glass crystals were collected by filtration, washed three times with water, and then dried to give the title compound. 12 g.
DESCRIPTION 61 Methyl 5-((D¡methylamino) sulfonyl-2-hydroxybenzoate (D61) A solution of 33% dimethylamine (1.53 ml, 9.97 mmol) in water was added dropwise to 5-. { methyl chlorosulfonyl) -2-hydroxybenzoate (can be prepared as described in the description 60; 500 mg, 2.00 mmol) in dichloromethane (20 ml) at 25 ° C, and the mixture was allowed to stir at 25 ° C for 2 hr . The mixture was then concentrated under vacuum to give the title compound as a crude product. 260 mg.
MS (electrospray): m / z [M + H] + = 260 DESCRIPTION 62 5-f (Dimethylamino) sulfonyl-2 - [(phenylmethyl) oxy1 benzoate methyl (D62) K2CO3 (139 mg, 1.00 mmol) was added to a stirred solution of methyl 5 - [(dimethylamino) sulfonyl] -2-hydroxybenzoate (can be prepared as described in the description 61; 260 mg, 1.00 mmol) in acetone ( 30 mL), followed by the addition of (bromomethyl) benzene (172 mg, 1.00 mmol). The mixture was heated to reflux for 6 hr, and then cooled to room temperature. The mixture was filtered, and the filtrate was concentrated to give the title compound as a colorless oil. 300 mg.
MS (electrospray): m / z [M + H] + = 350 DESCRIPTION 63 5-f (dimethylamino) sulfonyl-2-t (phenylmethyl) oxy-benzoic acid (D63) LiOH (20.56 mg, 0.86 mmol) was added to a stirred solution of methyl 5 - [(dimethylamino) sulfonyl] -2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in description 62, 300 mg, 0.86 mmol) in a mixture of tetrahydrofuran and water (3: 1, 40 ml). The mixture was heated at 50 ° C for 6 hr, and then diluted with ethyl acetate (50 ml). Aqueous HCI at 10% was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4 and concentrated to give the title compound as a white solid. 230 mg.
MS (electrospray): m / z [M + H] + = 336 DESCRIPTION 64 2-Hydroxy-5- (4-morpholinylsulfonyl) methyl benzoate (D64) Morpholine (174 mg, 2.00 mmol) was added dropwise to methyl 5- (chlorosulfonyl) -2-hydroxybenzoate (can be prepared as described in the description 63; 500 mg, 2.00 mmol) in dichloromethane (20 ml) 25 ° C, and the mixture was allowed to stir at 25 ° C for 2 hr. The mixture was then concentrated under vacuum to give the crude title compound. 350 mg.
MS (electrospray): m / z [M + H] + = 302 DESCRIPTION 65 5- (4-Morpholinylsulfonyl) -2-methyl f (phenylmethyl) oxybenzoate (D65) K2CO3 (138 mg, 1.00 mmol) was added to a stirred solution of methyl 2-hydroxy-5- (4-morpholinylsulfonyl) benzoate (can be prepared as described in the description 64, 300 mg, 1.00 mmol) in acetone (20 ml), followed by the addition of (bromomethyl) benzene (170 mg, 1.00 mmol). The mixture was heated to reflux for 16 hr, and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated to give the title compound as a colorless oil. 380 mg.
MS (electrospray): m / z [M + H] + = 392 DESCRIPTION 66 5- (4-morpholinylsulfonyl) -2 - [(phenylmethyl) oxnbenzoic acid (D66) LiOH (23.25 mg, 0.97 mmol) was added to a stirred solution of methyl 5- (4-morpholinylsulfonyl) -2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in the description 65; 380 mg, 0.97. mmoles) in a mixture of tetrahydrofuran and water (3: 1, 40 ml). The mixture was heated at 50 ° C for 6 hr, and then diluted with ethyl acetate (50 μm). 10% aqueous HCl was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO 4 and concentrated to give the title compound as a white solid. 250 mg.
MS (electrospray): m / z [M + H] + = 378 DESCRIPTION 67 Methyl 2-hydroxy-5- (1-piperidinylsulfonyl) benzoate (D67) Piperidine (849 mg, 9.97 mmol) was added dropwise to methyl 5- (chlorosulfonyl) -2-hydroxybenzoate (can be prepared as described in the description 60, 500 mg, 2.00 mmol) in dichloromethane (20 ml) 25 ° C, and the mixture was allowed to stir at 25 ° C for 2 hr. The mixture was then concentrated under vacuum to give the title compound as a crude product. 430 mg.
MS (electrospray): m / z [M + H] + = 300 DESCRIPTION 68 Methyl 2-f (phenylmethyl) oxy-1-5- (1-piperidinylsulfonyl) benzoate (D68) K2CO3 (203 mg, 1.47 mmol) was added to a stirred solution of methyl 2-hydroxy-5- (1-piperidinylsulfonyl) benzoate (can be prepared as described in the description 67; 400 mg, 1.34 mmol) in acetone (20 ml), followed by the addition of (bromomethyl) benzene (251 mg, 1.47 mmol). The mixture was heated to reflux for 16 hr, and then cooled to room temperature. The mixture was filtered and the filtrate was concentrated to give the title compound as a colorless oil. 300 mg.
MS (electrospray): m / z [M + H] + = 390 DESCRIPTION 69 2-R (phenylmethyl) oxy1-5- (1-piperidinylsulfonylbenzoic acid (D69)) LiOH (20.29 mg, 0.847 mmol) was added to a stirred solution of methyl 2 - [(phenylmethyl) oxy] -5- (1-piperidinylsulfonyl) benzoate (can be prepared as described in description 68; 330 mg, 0.85. mmoles) in a mixture of tetrahydrofuran and water (3: 1, 40 ml). The mixture was heated at 50 ° C for 6 hr, and then diluted with ethyl acetate (50 ml). Aqueous HCI at 10% was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4 and concentrated to give the title compound as a white solid. 220 mg.
MS (electrospray): m / z [M + H] + = 376 DESCRIPTION 70 Methyl 2-hydroxy-5 - [(4-methyl-1-piperazinyl) sulfonylbenzoate (D70) Methyl 5- (chlorosulfonyl) -2-hydroxybenzoate (can be prepared as described in the description 60; 500 mg, 1.995 mmol) was added to a stirred solution of 1-methylpiperazine (200 mg, 2.00 mmol) in dichloromethane (20 ml). The mixture was stirred for 0.5 hr, and then concentrated under reduced pressure to give the title compound as a colorless oil. 430 mg.
MS (electrospray): m / z [M + H] + = 315 DESCRIPTION 71 Methyl 5-f (4-Methyl-1-piperazinyl) sulfonin-2 - [(phenylmethyl) oxy] benzoate DEAD (0.24 ml, 1.51 mmol) was slowly added to a mixture of methyl 2-hydroxy-5 - [(4-methyl-1-piperazinyl) sulfonyl] benzoate (can be prepared as described in the description 70; 430 mg , 1.37 mmol), Ph3P (395 mg, 1.51 mmol) and phenylmethanol (163 mg, 1505 mmol) in toluene (15 ml) cooled in an ice bath at 0 ° C. The mixture was stirred for 2 hr at room temperature. Ether was added to the mixture and the mixture was filtered. The filtrate was evaporated to give the title compound. 260 mg.
MS (electrospray): m / z [M + H] + = 405 DESCRIPTION 72 5 - [(4-Methyl-1-piperazinyl) sulfonin-2-r (phenylmethyl) oxy-1-benzoic acid (D72) LiOH (15.39 mg, 0.64 mmol) was added to a stirred solution of 5- [. { Methyl 4-methyl-1-piperazinyl) sulfonyl] -2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in the description 71; 260 mg, 0.64 mmol) in a mixture of tetrahydrofuran and water (3: 1, 40 mi). The mixture was heated at 50 ° C for 6 hr and then diluted with ethyl acetate (50 ml). Aqueous HCI at 10% was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over MgSO4 and concentrated to give the title compound as a white solid. 120 mg.
MS (electrospray): m / z [M + H] + = 391 DESCRIPTION 73 (2) -2-r (1,1-dimethylethyl-1,1-dimethyl ethyl ((4-r (phenylmethyl) oxy] -1,3-t (3-pyridinylamino) carboninphenyl) oxy) metill-1-pyrrolidinecarboxylate (D73) Sodium hydride (44.9 mg, 1.87 mmol) was added to a solution of 5-hydroxy-2 - [(phenylmethyl) oxy] - / V-3-pyridinylbenzamide (can be prepared as described in example 29; 500 mg, 1.56 mmole) in dimethyl sulfoxide (8 ml) at 0 ° C and the mixture was stirred at room temperature for 1 hr. (2R) -2- (1,1-dimethylethyl 1,5-chloro-phenyl sulfonyl] oxy] methyl] -1-pyrrolidinecarboxylate (555 mg, 1.56 mmol) in dimethyl sulfoxide (7 ml) added dropwise, and the mixture was stirred at 75 ° C for 18 h. The mixture was poured into water (100 ml) and extracted with ethyl acetate. The organic layer was dried, and concentrated to obtain crude product, which was purified by chromatography on silica gel (dichloromethane / methanol = 50: 1) to give the title compound as a yellow oil. 0.55 g.
MS (electrospray): m / z [M + H] + = 504.0.
DESCRIPTION 74 (2S) -2-r (1,1-dimethyl ethyl (1-4-r (phenylmethyl) oxy-1-3-r (3-pyridinylamino) carbonylphenyl) oxy) methyl-1-pyrrolidinecarboxylate (D74) Sodium hydride (36.0 mg, 1.50 mmol) was added to a solution of 5-hydroxy-2 - [(phenylmethyl) oxy] - / \ / - 3-pyridinylbenzamide (can be prepared as described in Example 29; 400 mg , 1.25 mmol) in dimethyl sulfoxide (8 ml) at 0 ° C, and the mixture was stirred at room temperature for 1 hr. (2S) -2- (1,1-dimethylethyl (444 mg, 1.25 mmol) in dimethyl sulfoxide (7 ml) was added (2S) -2- ( { [(4-chlorophenyl) sulfonyl] oxy} methyl) -1-pyrrolidinecarboxylate (444 mg, 1.25 mmol) in dimethyl sulfoxide (7 ml). added to the solution dropwise, and the mixture was stirred at 75 ° C for 18 hr. The mixture was poured into water (100 ml), extracted completely with ethyl acetate. The organic layer was dried and concentrated to obtain a product crude, which was purified by chromatography on silica gel (dichloromethane / methanol = 50: 1) to give the title compound as a yellow oil. 0.60 g.
MS (electrospray): m / z [M + H] + = 504.1.
DESCRIPTION 75 Metiir2 - ((4-l (phenylmethyl-3-r (3-pyridinylamino) carbonyl-1-phenyl) oxy) ethyl-1-carbamate 1,1-dimethylethyl ester (D75) To a solution of 5-hydroxy-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in Example 44; 200 mg, 0.62 mmol) in dimethyl sulfoxide (8 ml) is added sodium hydride (17.98 mg, 0.75 mmol) at 0 ° C and the mixture was stirred at room temperature for 1 hr. 2-[. { [(1, 1-Dimethylethyl) oxy] carbonyl} (methyl) amino] ethyl 4-methylbenzenesulfonate (247 mg, 0.75 mmol) in dimethyl sulfoxide (8 mL) was added dropwise to the solution, and the mixture was stirred at 75 ° C for 18 hr. The mixture was poured into water (100 ml), extracted completely with ethyl acetate. The organic layer was dried and concentrated to obtain a crude product. The crude product was purified by chromatography on silica gel (dichloromethane / methanol = 15: 1) to give the title compound as a yellow oil. 140 mg.
MS (electrospray): m / z [M + H] + = 478.2.
DESCRIPTION 76 4-Methylbenzenesulfonate 2- (r2- (. {4-f (phenylmethyl) oxy] -3-r (3-pyridinylamino) carboninphenyl> oxy) ethyl loxy> ethyl (D76) Potassium hydroxide (0.15 g, 2.62 mmole) was added to a solution of 5-hydroxy-2 - [(phenylmethyl) oxy] - / V-3-pyridinylbenzamide (can be prepared as described in example 44; 0.7 g, 2.19 mmole) in methanol. The mixture was stirred for 0.5 hr. The mixture was evaporated and the residue was dissolved in dimethylformamide. 2,2'-Oxybis (ethane-2,1-diyl) bis (4-methylbenzenesulfonate) (1.36 g, 3.28 mmol) was added slowly and the mixture was stirred overnight. The solvent was evaporated to give the title compound as a crude product. 420 mg.
MS (electrospray): m / z [M + H] + = 563 DESCRIPTION 77 (2- (r2 - ((4-r (Phenylmethyl) oxy] -1-3-r (3-pyridinylamino) carboninphenyl) oxy) ethynoxy) ethyl) imidodicarbonate of Bis (1,1-dimethylethyl) (D77) 4-Methylbenzenesulfonate 2-. { [2- ( { 4 - [(phenylmethyl) oxy] -3 - [(3-pyridinylamino) carbonyl] phenyl} oxy) ethyl] oxy} ethyl (can be prepared as described in the description 76; 500 mg, 0.89 mmol) was dissolved in N, N-dimethylformamide (10 ml). Di-tert-butyl iminodicarbonate (193 mg, 0.89 mmol) and Cs2CO3 (290 mg, 0.89 mmol) were added. The reaction mixture was heated at 60 ° C for 3 hr. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give the title compound as an oil. 360 mg.
EM (electroaspersion): m / z [MH-100] + = 508 DESCRIPTION 78 2-f (Phenylmethyl) oxy-5- (4-pyridinyl) benzoate of phenylmethyl (D78) Na 2 CO 3 (0.53 g, 5.00 mmol), followed by pyridin-4-ylboronic acid (0.34 g, 2.75 mmol) and Pd (Ph 3 P) 4 (0.144 g, 0.125 mmol) were added to a mixture of 2- (benzyloxy) -5 benzyl bromobenzoate (can be prepared as described in the description 4; 1.0 g, 2.50 mmol) in 1,4-dioxane (25 ml) and water (5 ml) under nitrogen. After the addition, the mixture was stirred at 90 ° C for 4 hours. The reaction mixture was evaporated to give crude brown product which was purified by chromatography (silica gel, 40 g, eluent: ethyl acetate / petroleum ether = 1: 2, 1.2 L) to give the title compound as a solid White. 0.81 g.
MS (electrospray): m / z [M + H] + = 396 DESCRIPTION 79 2-f (phenylmethyl) oxy1-5- (4-pyridinyl) benzoic acid (D79) Solid LiOH (0.79 g, 18.77 mmol) was added to a stirred solution of phenylmethyl 2 - [(phenylmethyl) oxy] -5- (4-pyridinyl) benzoate (can be prepared as described in description 78; 0.81 g, 1.88 mmoles) in tetrahydrofuran (50 ml) and water (10 ml) in air at room temperature. The reaction mixture was stirred at 70 ° C overnight. After the reaction mixture was cooled to room temperature, the solvent was removed and the residue was dissolved in water (100 ml) and stirred in an ice-water bath. 1 N HCl (aq.) Was added to adjust the pH to 4. The solid was filtered, and dissolved in ethyl acetate (80 mL). The solution was dried over Na 2 SO 4) filtered and concentrated under reduced pressure to give the title compound as a white solid, 486 mg.
MS (electrospray): m / z [M + H] + = 305.9 DESCRIPTION 80 (3-Aminopyridin-2-yl) methanol (D80) 3-aminopicolinic acid (145 mg, 1.05 mmol) was carefully added in 3 aliquots to a suspension of LiAIH4 (143 mg, 3.78 mmol) in dry tetrahydrofuran (6 mL). The resulting mixture was stirred at 15 ° C overnight. After cooling in an ice bath, the mixture of reaction was quenched with the careful addition of water (1 ml) dropwise, followed by 15% aqueous NaOH (1 ml), and then water (3 ml). The resulting solid was filtered and washed several times with tetrahydrofuran. The filtrate was concentrated. The residue was purified by flash chromatography on silica gel using 5% CH3OH (NH3) / ethyl acetate as eluent to give the title compound as a yellow oil. 10 mg.
MS (electrospray): m / z [M + H] + = 125 DESCRIPTION 81 (3-Aminopyridin-4-yl) methanol (D81) 3-Aminoisonicotinic acid (1 g, 7.24 mmol) was carefully added in 3 aliquots to a suspension of LiAIH4 (0.99 g, 26.1 mmol) in dry tetrahydrofuran (40 mL). The resulting mixture was stirred at 15 ° C overnight. After cooling in an ice bath, the reaction mixture was quenched with the careful addition of water (1 ml) dropwise, followed by 15% aqueous NaOH (1 ml), and then water (3 ml). The resulting solid was filtered and washed several times with tetrahydrofuran. The filtrate was concentrated to give oil, which was purified by flash chromatography on silica gel using 5% CH3OH (NH3) / ethyl acetate as eluent to give the title compound as a yellow oil. 610 mg.
MS (electrospray): m / z [M + H] + = 125 DESCRIPTION 82 5-Bromo-2-. { (3-fluorophenyl) methyl f (3-fluorophenyl) methyloxy) benzoate (D82) Solid potassium carbonate (2.76 g, 20 mmol) was added to a stirred solution of 5-bromo-2-hydroxybenzoic acid (1 g, 4.61 mmol) in acetone (20 mL) at 20 ° C. The reaction mixture was stirred at 20 ° C for 10 min, and then 1- (bromomethyl) -3-fluorobenzene (1.92 g, 10.14 mmol) was added dropwise. The reaction mixture was stirred at 71 ° C for 18 hr. After cooling to room temperature, the mixture was filtered. The filtrate was concentrated to give a colorless oil. The crude product was added to a column of silica gel and eluted with hexane / ethyl acetate (100: 5 then 20: 1) to give the title compound as a white solid. 1.65 g.
MS (electrospray): m / z [M + Na] + = 454.8, 456.8 DESCRIPTION 83 5-Bromo-2- (f (3-fluorophenyl) methoxy) benzoic acid (D83) Solid LiOH (0.50 g, 20.95 mmol) was added in a charge to a stirred solution of 5-bromo-2-. { [(3-fluorophenyl) methyl] oxy} (3-fluorophenyl) methyl benzoate (can be prepared as described in description 82; 1.65 g, 3.81 mmol) in tetrahydrofuran (15 ml) and water (5 ml) in air at 20 ° C. The reaction mixture was stirred at 71 ° C for 16 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (200 ml). Aqueous HCI at 10% was added to the mixture to adjust the pH to 2. The organic phase was isolated, washed with brine, dried over Na2SO4 and concentrated to give the title compound as a white solid. 1.5 g.
MS (electrospray): m / z [M + H] + = 324.8, 326.8, DESCRIPTION 84 5-Bromo-2- (f (2-fluorophenyl) methoxy) benzoate (2-fluorophenyl) methyl (D84) 1- (Bromomethyl) -2-fluorobenzene net (1533 mg, 8.11 mmol) was added over 1 min to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (800 mg, 3.69 mmol) and potassium carbonate (1274 mg, 9.22 mmole) in acetone (60 ml) in air at room temperature. The reaction mixture was stirred at 70 ° C overnight. The reaction mixture was filtered. The filtrate was evaporated and the residue was dissolved in diethyl ether (30 ml) and evaporated again. The residue was dried under vacuum to give the title compound as a white solid. 1.74 g.
MS (electrospray): m / z [M + H] + = 433, [M + Na] + = 455 DESCRIPTION 85 5-bromo-2- acid. { f (2-fluorophenyl) methynoxy) benzoic acid (D85) Solid LiOH (0.24 g, 10.16 mmol) was added to a stirred solution of 5-bromo-2-. { [(2-fluorophenyl) methyl] oxy} (2-fluorophenyl) methyl benzoate (can be prepared as described in the description 84; 1 g, 2.03 mmol) in tetrahydrite break (30 ml) and water (10 ml) in air at room temperature. The reaction mixture was stirred at 70 ° C overnight. After cooling to room temperature, the solvent was removed to obtain a solid, which was dissolved in water (20 ml) and stirred in an ice-water bath. 1 M HCl (aq.) Was added to adjust the pH to 4. The solid was filtered and dried under vacuum to give the title compound as a white solid. 695 mg.
MS (electrospray): m / z [M + Na] + = 347.0, 348.9 DESCRIPTION 86 5-Bromo-2-. { (4-fluorophenyl) methyl-oxo) benzoate (4-fluorophenyl) methyl (D86) Method A 1- (Bromomethyl) -4-fluorobenzene (1533 mg, 8.1 mmol) was added over 1 min to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (800 mg, 3.69 mmol) and potassium carbonate. (1274 mg, 9.22 mmol) in acetone (60 ml) in air at room temperature. The mixture of The reaction was stirred at 70 ° C overnight. After filtration, the filtrate was evaporated to give a solid, which was dried under vacuum to give the title compound as a white solid. 1.56 g.
MS (electrospray): m / z [M + Na] + = 455 Method B Cesium carbonate (7.51 g, 23.04 mmol) and 4-fluorobenzyl bromide (2.51 ml, 20.27 mmol) were added to a solution of 5-bromosalicylic acid (2 g, 9.22 mmol) in acetone (50 ml). The mixture was stirred for 2 hours, the solvent was removed under vacuum and the residue redissolved in water (20 ml) and ethyl acetate (50 ml). The organic layer was separated, dried (MgSO4) and the solvent was removed under vacuum to give a solid. Trituration with 3: 1 hexane / ethyl acetate gave the title compound as a white solid. 2.62 g.
MS (electrospray): m / z [M + Na] + = 457 DESCRIPTION 87 5-bromo-2- (f (4-fluorophenyl) methoxy) benzoic acid (D87) Solid LiOH (0.23 g, 9.58 mmol) was added to a stirred solution of 5-bromo-2-. { [(4-fluorophenyl) methyl] oxy} (4-fluorophenyl) methyl benzoate (can be prepared as described in the description 86; 1 g, 1.92 mmol) in tetrahydrofuran (30 ml) and water (10 ml) in air at room temperature. The reaction mixture was stirred at 70 ° C overnight. After cooling to room temperature, the solvent was removed to obtain a solid which was dissolved in water (20 ml) and stirred in a water bath with ice. 1 N HCl (aq.) Was added to adjust the pH to 4. The solid was filtered and dried under vacuum to give the title compound as a gray solid. 674 mg.
MS (electrospray): m / z [M + Na] + = 347.0, 348.9 Method B Lithium hydroxide (0.43 g, 18.14 mmol) was added to a solution of 5-bromo-2-. { [(4-fluorophenyl) methyl] oxy} (4-fluorophenyl) methyl benzoate (can be prepared as described in description 86) (2.62 g, 6.05 mmol) in water (5 ml) and tetrahydrofuran (20 ml). The mixture was stirred overnight and the solvent was removed under vacuum. The residue was redissolved in water (30 ml) and acidified to pH = 2 using 1 N HCl and then extracted with ethyl acetate (3 x 25 ml). The combined organic layers were dried (MgSO4) and the solvent was removed under vacuum to give the title compound as a white solid. 1.97g.
MS (electrospray): m / z [M + H] + = 324/326 DESCRIPTION 88 5-Bromo-2- (f (3, 4-d-fluoro-phenyl) -methyl-oxo> (3,4-difluorophenyl-D-methyl) benzoate (D88) 4- (Bromomethyl) -1,2-di-fluorobenzene (1526 mg, 7.37 mmol) was added over 1 min to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (800 mg, 3.69 mmol) and potassium carbonate (1274 mg, 9.22 mmol) in acetone (60 ml) in air at room temperature. The reaction mixture was stirred at 70 ° C overnight. After filtration, the filtrate was evaporated to give a solid, which was dried under vacuum to give the title compound as a white solid. 2.0 g.
MS (electrospray): m / z [M + Na] + = 491 Method B To a stirred solution of 5-bromo-2-hydroxybenzoic acid (1.8 g, 8.29 mmol) in acetone (50 mL) at room temperature was added potassium carbonate (2.87 g, 20.74 mmol) followed by 4- (bromomethyl) -1 , 2-difluorobenzene (2.34 ml, 18.25 mmol). The mixture was stirred at room temperature for 30 min and then heated to reflux for 15 hr. The solid was filtered and washed with acetone (3 x 50 mL). The organic layer was evaporated under reduced pressure and the oil was purified by chromatography using a silica cartridge, eluting with 0-15% ethyl acetate / isohexane to give a clear oil, which solidified on standing to give the title compound . 3.9 g.
MS (electroaspersion): m / z [M + H] + no mass ions were observed.
DESCRIPTION 89 5-bromo-2- acid. { f (3,4-difluorophenyl) methyloxy > benzoic (D89) Solid LiOH (0.26 g, 10.86 mmol) was added to a stirred solution of 5-bromo-2-. { [(3,4-difluorophenyl) methyl] oxy} benzoate (3,4-diforophenyl) methyl (can be prepared as described in the description 88; 1.2 g, 2.17 mmol) in tetrahydrofuran (30 ml) and water (10 ml) in air at room temperature. The reaction mixture was stirred at 70 ° C overnight. After cooling to room temperature, the solvent was removed. The residue was dissolved in water (20 ml) and stirred in an ice-water bath. 1 HCl (aq) was added to the mixture to adjust the pH to 4. The solid was filtered and dried under vacuum to give the title compound as a white solid. 730 mg.
EM (electrospray): m / z [M + Na] + = 365 Method B Water (50 ml) and lithium hydroxide (0.60 g, 24.93 mmol) were added to a solution of 5-bromo-2-. { [(3,4-difluorophenyl) methyl] oxy} (3,4-difluorophenyl) methyl benzoate (can be prepared by the disclosure 88; 3.9 g, 8.31 mmol) in tetrahydrofuran (150 ml). The mixture was refluxed for 2 hours. The mixture was allowed to cool and was diluted with ethyl acetate (200 ml) and this mixture was then acidified to pH = 1 using aqueous HCl 2. The organics were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The organics were combined, dried (MgSO 4) and evaporated under reduced pressure to give the title compound as a white solid. 2.9 g. The residue contains some benzyl alcohol.
MS (electrospray): m / z [M + H] + = 343 DESCRIPTION 90 (3-Methyl-4-isoxazolyl) carbamate, 1-dimethylethyl (D90) Diphenylphosphrazidate (1083 mg, 3.93 mmol) and triethylamine (0.55 mL, 3.93 mmol) were added to a stirred solution of 3-methylisoxazole-4-carboxylic acid (500 mg, 3.93 mmol) in tert-butanol (30 mL) at 50 ° C. After the addition, the solution was heated at 90 ° C for 6 hours. The reaction mixture was evaporated to remove solvent and the residue was purified by column chromatography (silica gel, 40 g, eluent: dichloromethane / methanol = 50: 1, 500 ml) to give the title compound as a white solid. 517 mg.
MS (electrospray): m / z [M + H] + = 199 DESCRIPTION 91 3-Methyl-4-isoxazolamine (D91) HCl gas in ethanol (10 ml, 13 mmol) was carefully added to 1, -dimethylethyl (3-methyl-4-isoxazolyl) carbamate (it can be prepared as described in the description 90; 517 mg, 2.07 mmol) in a Water bath with ice. After the addition, the solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain colorless gum, which was dissolved in water (10 ml), then aqueous ammonia solution (30%) was added to adjust the pH to 9. The solution was concentrated to give crude title compound as a yellow solid. 560 mg.
DESCRIPTION 92 1,1-dimethylethyl (5-Methyl-4-isoxazolyl) carbamate (D92) Diphenyl phosphorazidate (1083 mg, 3.93 mmol) and triethylamine (0.55 mL, 3.93 mmol) was added to a stirred solution of 5-methylisoxazole-4-carboxylic acid (500 mg, 3.93 mmol) in tert-butanol (30 mL) at 50 ° C. After the addition, the solution was heated at 90 ° C for 6 hours. The reaction mixture was diluted with saturated NaHCO 3 solution (50 ml) and then extracted with ethyl acetate (60 ml x 5). The combined organic phases were dried over anhydrous MgSO 4 and concentrated. The residue was purified by column chromatography (silica gel, 40 g, eluent: dichloromethane / methanol = 100: 1, 1.3 L) to give the title compound as a white solid. 61 mg.
MS (electrospray): m / z [M + H] + = 199.0 DESCRIPTION 93 5-Methyl-4-isoxazolamine (D93) HCI gas in ethanol (5 ml, 6.50 mmol) was added carefully in 1,1-dimethylethyl (5-methyl-4-isoxazolyl) carbamate (can be prepared as described in the description 92; 161 mg, 0.81 mmol) in a water bath with ice. The solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was dissolved in water (10 ml). 30% aqueous ammonia solution was added to adjust the pH to 9. The solution was then concentrated to give the title compound as a yellow solid. 142 mg.
DESCRIPTION 94 4-Nitroisoxazole (D94) Isoxazole (4.64 ml, 72.4 mmol) was dissolved in trifluoroacetic anhydride (30 ml) and ammonium nitrate (6.37 g, 80 mmol) was added in 0.5 g portions, maintaining the reaction temperature between 25 ° C ~ 30 ° C.
Another batch of ammonium nitrate (3.6 g) was then added. Approximately one third of the reaction solution was poured into ice water, and extracted with dichloromethane (60 ml x 4). The extracts were combined, washed with water (80 ml x 3), dried over anhydrous MgSO 4, and concentrated to give the title compound as a yellow solid. 0.9 g.
DESCRIPTION 95 4-lsoxazolamine (D95) 4-Nitroisoxazole (can be prepared as described in the description 94; 850 mg, 7.45 mmol) was added to a solution of ammonium chloride (9169 mg, 171 mmol) in water (60 ml). The resulting suspension was cooled to 0 ° C, and zinc (4142 mg, 63.3 mmol) was added in portions while maintaining the temperature below 5 ° C. After the addition, the mixture was stirred at 0-5 ° C for 2 hours. The reaction mixture was then filtered and the filtrate was extracted with ethyl acetate (100 ml x 4). The organic phase was washed with water (100 ml x 2), dried over anhydrous MgSO 4 and concentrated to give the title compound as a brown oil, 535 mg.
DESCRIPTION 96 Phenylmethyl 5-formyl-2-f (phenylmethyl) oxy] benzoate (D96) Cesium carbonate (14.71 g, 45.1 mmol) and benzyl bromide (4.47 mL, 37.6 mmol) were added dropwise to a solution of 5-formyl-2-hydroxybenzoic acid (2.5 g, 15.05 mmol) in dimethylformamide (40 ml). ). The mixture was stirred for 24 hours. The dimethylformamide was removed under vacuum and the residue redissolved in ethyl acetate (50 ml), washed with water (3 x 30 ml), dried (MgSO 4) and the solvent removed under vacuum to give an off-white solid. Trituration with 6: 1 isohexane / ethyl acetate gave the title compound as a white solid. 4.20 g.
MS (electrospray): m / z [M + H] + = 347 DESCRIPTION 97 5-formyl-2-f (phenylmethyl) oxyflbenzoic acid (D97) Lithium hydroxide (207 mg, 8.66 mmol) and water (2.5 ml) were added to a solution of phenylmethyl 5-formyl-2 - [(phenylmethyl) oxy] benzoate (can be prepared as described in description 96) (1 g, 2.89 mmol) in tetrahydrofuran (10 ml) and methanol (2.5 ml). The mixture was stirred overnight. The tetrahydrofuran / methanol was removed under vacuum and the remaining aqueous solution was acidified to pH = 1 and extracted with ethyl acetate (3 x 20 mL). The solvent was removed under vacuum to give the title compound as a solid white. 1.1 g.
EM (electroaspersion): m / z [M-H] + DESCRIPTION 98 3- (4-Hydroxy-3-r (3-pyridinylamino) carbonyl-1-phenyl) -propanoic acid ethyl ester (D98) To a suspension of (2Z) -3-. { 4 - [(phenylmethyl) oxy] -3 - [(3-pyridinylamino) carbonyl] phenyl} Ethyl 2-propanoate (can be prepared as described in Example 68; 160 mg, 0.40 mmol) in methanol (10 mL) was added Pd / C (20 mg). The mixture was placed under a nitrogen atmosphere for 5 hours. The catalyst was removed by filtration through Celite and the solvent was removed under vacuum to give the title compound as a pale yellow solid. 119 mg.
MS (electrospray): m / z [M + H] + = 314 DESCRIPTION 99 Methyl 5-Bromo-2- (r (1S) -1-phenylethyloxy) benzoate (D99) (1 R) -1-Phenylethanol (3.33 g, 27.30 mmole) and Ph3P (7.15 g, 27.3 mmole) was added to a solution of methyl 4-bromo-2-hydroxybenzoate (3 g, 12.98 mmole) in dichloromethane (50 g). my). The solution was cooled to 0 ° C then DIAD (5.30 mL, 27.30 mmol) was added. The mixture was allowed to warm to room temperature and then stirred overnight. The solvent was removed under vacuum and purified by column chromatography (5% ethyl acetate / hexane to 20% ethyl acetate / hexane) to give the title compound as a colorless oil. 4.56 g. It contained trace of ethyl acetate and Ph3P by NMR.
MS (electrospray): m / z [M + H] + = 357/359 DESCRIPTION 100 2-fr (3,4-Difluorophenyl) methyloxy > -5-formylbenzoate of (3,4-difluoropheniQmethyl (Di 00) Cesium carbonate (17.65 g, 54.2 mmol) and 4- (bromomethyl) -1,2-difluorobenzene (5.78 mL, 45.1 mmol) were added to a solution of 5-formyl-2-hydroxybenzoic acid (3 g, 18.06 mmol) in dimethylformamide (100 ml) at room temperature. The mixture was stirred at room temperature overnight. The mixture was then filtered, the dimethylformamide was evaporated and the residue was diluted with ethyl acetate (100 ml) and washed with water (3 x 50 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure to give an oil which solidified on standing. The solid was triturated with an 8: 1 mixture of hexane / ethyl acetate. The solid was filtered and dried in air under vacuum to give the title compound as a white solid. 7 g.
MS (electrospray): m / z [M + H] + = 419 DESCRIPTION 101 2- (f (3,4-difluorophenyl) methyloxy> -5-formylbenzoic acid (D101) To a solution of 2-. { [(3,4-difluorophenyl) methyl] oxy} -3- (3,4-difluorophenyl) methyl formylbenzoate (can be prepared by the description 100; 7 g; 16.73 mmol) in tetrahydrofuran (50 ml) was added lithium hydroxide (1202 g, 50.2 mmol) followed by methanol ( 2.50 mi) and water (2.5 mi). The mixture was stirred at room temperature overnight. The mixture was then evaporated under reduced pressure to one third of its volume. The mixture was diluted with water (50 ml) and acidified to pH = 1 using 2M aqueous HCl. The solid formed was filtered, washed with water and dried with air under vacuum to give a white solid. 4.85 g.
MS (electrospray): m / z [M + H] + = 293 DESCRIPTION 102 5-Bromo-2- (f (2,4-difluorophenyl) methyl-oxo) benzoate (2,4-difluorophenyl-methyl) (D102) To a solution of 5-bromo-2-hydroxybenzoic acid (2.5 g, 1.52 mmol) in acetone (100 mL) was added potassium carbonate (3.98 g, 28.8 mmol) and 1- (bromomethyl) -2,4-difluorobenzene ( 3.25 ml, 25.3 mmol). The mixture was refluxed for 4 hours. Upon cooling, the mixture was filtered to remove the carbonate, the solid was washed with acetone (50 ml). The organic compounds were evaporated under reduced pressure to give a white solid 5.39 g. No attempt was made to purify this compound, it was taken as such.
MS (electrospray): m / z [M + H] + = 470 DESCRIPTION 103 5-bromo-2- (r (2,4-difluorophenyl) methyloxy) benzoic acid (D103) Lithium hydroxide (0.83 g, 34.5 mmol) and water (50 ml) were added to a solution of 5-bromo-2-. { [(2,4-difluorophenyl) methyl] oxy} (2,4-difluorophenyl) methyl benzoate (can be prepared by the description 102; 5.39 g, 1.49 mmol) in tetrahydrofuran (200 ml). The mixture was refluxed for 2 hr. The tetrahydrofuran was then stirred in a rotoevaporator and the aqueous mixture acidified to pH = 1 using 2M aqueous HCl. The solid formed was filtered, washed with water (2 x 50 ml) and dried in air under vacuum. The solid was triturated with diethyl ether to give a white solid. 3.1 9 · MS (electrospray): m / z [M + H] + = 344 DESCRIPTION 104 2- (f (4-Fluorophenyl) methyanoxy> -5-formylbenzoate (4-fluorophenyl) methyl (D104) Cesium carbonate (11.77 g, 36.1 mmole) and 1- (bromomethyl) -4-fluorobenzene (1.50 ml, 12.04 mmole) were added to a solution of 5-formyl-2-hydroxybenzoic acid (2 g, 12.04 mmole) in dimethylformamide (100 ml) at room temperature. The mixture was stirred at room temperature overnight. The mixture was filtered, the dimethylformamide was evaporated and the residue was diluted with ethyl acetate (100 ml) and washed with water (3 x 50 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure to give an oil which solidified on standing. The solid was triturated with an 8: 1 mixture of hexane / ethyl acetate. The solid was filtered and dried in air under vacuum to give the title compound as a white solid. 4.09 g.
MS (electrospray): m / z [M + H] "= 383 DESCRIPTION 105 Acid 2-. { ff4-fluorophenyl) methyloxy) -5-formylbenzoic acid (D105) Lithium hydroxide (0.75 g, 31.4 mmol), methanol (25 ml) and water (25 ml) were added to a solution of 2-. { [(4-fluorophenyl) meth] oxy} - (4-fluorophenyl) methyl formylbenzoate (can be prepared as described in the description 104; 4 g, 10.46 mmol) in tetrahydrofuran (100 ml). The The mixture was stirred at room temperature overnight. The mixture was evaporated to half its volume, diluted with water (100 ml) and acidified with 1 M aqueous hydrochloric acid to adjust the pH to 1. The mixture was stirred at room temperature and the solid formed was filtered, washed with water (50 ml) and dried with air under vacuum to give the title compound as a white solid. 2.85 g.
MS (electrospray): m / z [M + H] "= 273 DESCRIPTION 106 Methyl 5-formyl-2-hydroxybenzoate (D106) To a solution of 5-formyl-2-hydroxybenzoic acid (3 g, 18.06 mmol) in methanol (10 mL) was added H2SO (0.5 mL, 9.38 mmol). The solution was heated at 50 ° C for 18 hours. The solution was cooled and DCM (30 mL) and water (20 mL) were added. The organic layer was separated, washed with NaHCO 3 (10 mL), dried (MgSO 4) and the solvent removed under vacuum to give the title compound as a yellow solid. 3.1 g.
MS (electrospray): m / z, [M + H] + = 181 DESCRIPTION 107 4-Hydroxy-3-f (methyloxy) carbonyl-1-benzoic acid (D107) Sulfamic acid (1.83 g, 18.87 mmol) and 2-methyl-1-butene (1.20 mL, 11.10 mmol) were added to a solution of methyl 5-formyl-2-hydroxybenzoate (can be prepared as described in Example 1). description 106; 1 g, 5.55 mmoles) in tetrahydrofuran (20 ml), water (20 ml) and dimethyl sulfoxide (20 ml). The solution was cooled to 0 ° C and sodium chlorite (1.51 g, 16.65 mmol) in water (5 ml) was added. After 45 minutes at 0 ° C, the reaction mixture was quenched with saturated Na 2 S 203 solution (20 ml) and extracted with ethyl acetate (3 x 30 ml). The organic layer was dried (MgSO4) and the solvent was removed under vacuum to give the title compound as a solid. 1.09 g (moistened with DMSO / H2O).
EM (electroaspersion); m / z, [M + H] + = 197 DESCRIPTION 108 Methyl 2-hydroxy-5- (4-morpholinylcarbonyl) benzoate (D108) To a solution of 4-hydroxy-3 - [(methyloxy) carbonyl] benzoic acid (can be prepared as described in description 107, 1.31 g, 6.68 mmol) in N, N-dimethylformamide (10 mL) was added diisopropylethylamine ( 2.33 ml, 13.36 mmol), morpholine (1.75 ml, 20.03 mmol), HOBT (1.33 g, 8.68 mmol) and EDC (2.56 g, 13.36 mmol). The solution was stirred at room temperature for 18 hours then another equivalent of EDC was added (1.28 g, 13.38 mmol). The solution was stirred for another 6 hours, then ethyl acetate (20 ml) and water were added. The organic layer was separated, washed with water (3 ml), dried (MgSO 4) and the solvent removed under vacuum to give a gum. Purification by MDAP gave the title compound as a gum. 560 mg.
MS (electrospray): m / z, [M + H] + = 266 DESCRIPTION 109 2-. { methyl f (4-fluorophenyl) methyloxy) -5- (4-morpholinylcarbonyl) benzoate (D 09) To a solution of methyl 2-hydroxy-5- (4-morpholinylcarbonyl) benzoate (can be prepared as described in the description 108, 270 mg, 1.02 mmol) in acetone (3 mL) was added cesium carbonate (663 mg. , 2.04 mmol) and 4-fluorobenzyl bromide (0.16 ml, 1.32 mmol). The mixture was heated at 50 ° C for 2 hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (15 ml) and water (5 ml). The organic layer was dried and the solvent was removed under vacuum and the residue was purified by column chromatography (silicon, 4: 1 ethyl acetate / cyclohexane) to give the title compound as a yellow gum. 96 mg.
MS (electrospray): m / z, [M + H] + = 374 DESCRIPTION 110 2- (Methyl (2,4-difluorophenyl) methyloxy) -5- (4-morpholinylcarbonyl) benzoate (D110) To a stirred solution of methyl 2-hydroxy-5 ~ (4-morpholinylcarbonyl) benzoate (can be prepared as described in the description 108, 270 mg, 1.02 mmol) in acetone (3 mL) was added cesium carbonate (663 mg, 2.04 mmol) and 1- (bromomethyl) -2,4-difluorobenzene (0.17 mL, 1.32 mmol). The mixture was heated at 50 ° C for 2 hours, cooled and the solvent was removed under vacuum. The residue was partitioned between water (5 ml) and ethyl acetate (10 ml). The organic layer was dried (MgSO4) and the solvent was removed under vacuum to give a residue. Purification by column chromatography (silicon, 4: 1 ethyl acetate / cyclohexane) gave the title compound as a yellow gum. 100 mg.
MS (electrospray): m / z, [M + H] + = 392 DESCRIPTION 111 4- Acid. { l (4-fluorophenyl) methyloxy) -3-r (3-pyridinylamino) carboninbenzoic acid (D111) To a solution of 2-. { [(4-fluorophenyl) methyl] oxy} -5-formyl-N-3-pyridinylbenzamide (can be prepared as described in the example 82.00 mg, 0.29 mmol) in acetone (10 ml) was added potassium permanganate (67.7 mg, 0.43 mmol) as a 10 ml of water. The mixture was stirred at room temperature overnight. The mixture was quenched by the addition of 10 ml of 5% sodium sulfite solution. The solution was filtered through Celite and mixed with 1 ml of acetic acid. The mixture was evaporated to one third of its volume, water (20 ml) was added and the mixture was filtered to give the title compound as a white solid. It contains approximately 10% starting material and was used directly without further purification. 63 mg.
MS (electrospray): m / z [M + H] + = 367 DESCRIPTION 112 2- (methyl r (4-fluorophenyl) methyloxy-5-iodobenzoate (D112) To a solution of methyl 2-hydroxy-5-iodobenzoate (15 g, 53.9 mmol) in acetone (200 mL) was added 1- (bromomethyl) -4-fluorobenzene (9.95 mL, 81 mmol), potassium carbonate (14.91). g, 108 mmol) and the mixture was refluxed overnight. The mixture was allowed to cool and then filtered to remove the potassium carbonate. The solid potassium carbonate was washed with acetone (100 ml). The organic compounds were combined and evaporated under reduced pressure in a Buchi rotoevaporator to give a solid. The solid was taken up in ethyl acetate (500 ml) and the organic phase was washed with water (2 x 200 ml), dried (MgSO) and evaporated under pressure. reduced in a Buchi rotoevaporator. The solid obtained was recrystallized from cyclohexane to give the title compound as a white solid. 18.2 g.
MS (electrospray): m / z [M + H] "= 385 DESCRIPTION 113 2- (1- (4-fluorophenyl) methyloxy> -5- (1-r2- (4-morpholinyl) ethyn-1 H-pyrazole-4-methyl] -benzoate (D1 3) To a microwave flask was added 2-. { [(4-fluorophenyl) methyl] oxy} -5-Methyl iodobenzoate (can be prepared as described in the description 1 12; 0.5 g, 1.30 mmol), 4-. { 2- [4- (4,4,5,5-tetramethyl-1, 3,2-dioxoborolan-2-yl) -1 H-pyrazol-1-yl] ethyl} morpholine (0.60 g, 1.94 mmol), 1,2-dimethoxyethane (10 ml), tripotassium phosphate (0.55 g, 2.59 mmol) and PdCI2 (dppf) (0.08 g, 0.10 mmol). The mixture was sealed and heated at 120 ° C for 30 min under microwave conditions. The mixture was evaporated under reduced pressure in a Buchi rotoevaporator. The residue was taken up in ethyl acetate (50 ml) and washed with water (2 x 25 ml). The organic phase was evaporated and purified by chromatography using a Flashmaster, eluting with 0-25% methanol / dichloromethane to give the title compound as the main compound. This was used directly without further purification. 372 mg.
MS (electrospray): m / z [M + H] + = 440 DESCRIPTION 114 2- (R (4-fluorophenyl) methyloxy-5-f-1-r2- (4-morpholinyl etin-1 H-pyrazole-4-D-benzoic acid (D114) acid To a solution of 2-. { [(4-fluorophenyl) methyl] oxy} -5-. { 1- [2- (4-morpholinyl) ethyl] -1 H -pyrazol-4-yl} Methyl benzoate (can be prepared as described in 1 13; 372 mg, 0.85 mmol) in tetrahydrofuran (25 ml) was added lithium hydroxide (60.8 mg, 2.54 mmol), water (5 ml) and the mixture was mixed. refluxed for 4 hours. The mixture was evaporated under reduced pressure in a Buchi rotoevaporator. The residue was taken up in water (10 ml) and acidified using aqueous HCl 2 to pH 1. The solid formed was filtered, washed with water and dried in air under vacuum to give the title compound as a light brown solid. 70 mg.
MS (electrospray): m / z [M + H] + = 426 DESCRIPTION 115 2-. { methyl f (4-fluorophenyl) methynoxy) -5- (1 H -pyrazol-4-yl) benzoate (D 15) To a solution of 2-. { [(4-fluorophenyl) methyl] oxy} -5-methyl iodobenzoate (can be prepared as described in description 112; 1.4 g, 3.63 mmol) in 1,2-dimethoxyethane (40 mL) was added 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H-pyrazole -1-dimethylethyl carboxylate (3.20 g, 10.88 mmol), tripotassium phosphate (1.54 g, 7.25 mmol), PdCI2 (dppf) (0.6 g, 0.22 mmol) and the mixture was heated at 80 ° C for 6 h. hours. The temperature was raised to 90 ° C for 2 hours. Additional catalyst was added and the mixture was divided in two. A portion of 20 ml was subjected to 120 ° C for 30 min under microwave conditions. The second 20 ml portion was refluxed for 12 hr. Protected products of 1,1-dimethylethyl carboxylate were deprotected. The products were then combined and evaporated under reduced pressure in a Buchi rotoevaporator. The mixture was taken up in dichloromethane (20 ml), treated with trifluoroacetic acid (10 ml) and stirred at room temperature for 1 hour. The mixture was evaporated and purified using the Flashmaster eluting with 0-25% methanol / dichloromethane to give the title compound. 1-15 g.
MS (electrospray): m / z [M + H] + = 327 DESCRIPTION 116 2- (R (4-Fluorophenyl) methynoxy) -5- (1-f2- (methyloxy) ethyne-1H-pyrazol-4-yl) methyl benzoate (D116) To a solution of 2-. { [(4-fluorophenyl) methyl] oxy} -5- (1 H-pyrazol-4-yl) methyl benzoate (can be prepared as described in the description 115; 200 mg, 0.61 mmol) was added 2-bromoethylmethyl ether (0.10 ml, 1.23 mmol), carbonate potassium (254 mg, 1.84 mmol) and the reaction mixture was stirred at room temperature. The reaction mixture was then heated at 50 ° C for 5 hours. The reaction was filtered to remove the Potassium carbonate and organic compounds were evaporated in a Buchi rotoevaporator under reduced pressure. The solid was taken up in ethyl acetate (50 ml) and this was washed with water (1 x 25 ml). The organics were dried (MgSO 4) and evaporated under reduced pressure in a Buchi rotoevaporator to give the title compound. The crude product was used directly without further purification. 240 mg.
MS (electrospray): m / z [M + H] + = 385 DESCRIPTION 117 2-Hydroxy-5- (trifluoromethyl) benzoic acid (D117) Yodocyclohexane (29.4 ml, 227 mmol) was added to a solution of 2- (methyloxy) -5- (trifluoromethyl) benzoic acid (5 g, 22.71 mmol) in N, N-dimethylformamide (25 ml) and the mixture it was heated under reflux for 4 hours. After cooling, the reaction was evaporated under reduced pressure in a Buchi rotoevaporator. The residue was triturated with cyclohexane, and the solid obtained was filtered, washed with cyclohexane and dried in air under vacuum. 4.2 g.
MS (electrospray): m / z [M + H] "= 205 DESCRIPTION 118 (4-Fluorophenyl) methyl 2-. { f (4-fluorophenyl) methyloxy) -5- (trif (uoromethyl) benzoate (D118) To a solution of 2-hydroxy-5- (trifluoromethyl) benzoic acid (can be prepared as described in the description 1 17; 2 g, 9.70 mmol) in acetone (50 ml) was added 1- (bromomethyl) -4- fluorobenzene (4.04 g, 21.35 mmole), potassium carbonate (4.02 g, 29.1 mmole) and the reaction was heated to reflux overnight. The mixture was filtered to remove the solid potassium carbonate. The solid was washed with acetone (50 ml). The organics were combined and evaporated under reduced pressure in a Buchi rotoevaporator to give the title compound. The crude yellow oil was used directly without further purification. 4.1 g.
MS (electrospray): m / z [M + H] + = 423 DESCRIPTION 119 2- (f (4-fluorophenyl) methyloxy) -5- (trifluoromethyl) benzoic acid (D119) Lithium hydroxide (0.70 g, 29.1 mmol) and water (20 mL) were added to a solution of 2-. { [(4-fluorophenyl) methyl] oxy} -5- (trifluoromethyl) benzoate (4-fluorophenyl) methyl (can be prepared as described in the description 1 18; 4.1 g, 9.71 mmol) in tetrahydrofuran (100 ml) and the mixture heated to reflux for 2 hours. The mixture was evaporated under reduced pressure in a Buchi rotoevaporator. Water (100 ml) was added and the mixture acidified to pH = 1 using 2M aqueous hydrochloric acid. The precipitate was filtered and washed with water (2 x 50 mL). The solid was dried in air, under vacuum to give the title compound as a white solid. 2.39 g MS (electrospray): m / z [M + H] + = 315 DESCRIPTION 120 2- (f (4-Fluorophenyl) methyloxy) -5- (1-methyl-1H-pyrazol-4-yl) benzoate of (4- fluoropheniDmethyl (D120) A mixture of 5-bromo-2-. { [(4-fluorophenyl) methyl] oxy} benzoate (4-fluorophenyl) methylp (420 mg, 0.97 mmol), 1-methyl-4- (4) 4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) - H -pyrazole ( 208 mg, 1.00 mmol), tetrakis (triphenylphosphino) palladium (0) (34.7 mg, 0.03 mmol) and K2C03 (414 mg, 3 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred under nitrogen and heated at 90 ° C for 16 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (100 ml) and filtered. The filtrate was washed with water (50 ml) and brine (50 ml), dried over Na 2 SO 4 and concentrated to give the crude product. The crude product was purified by a column of silica gel (eluting with dichloromethane / methanol = 50: 1) to give the title compound as a white solid. 360 mg.
LC S: MH + = 435.0 DESCRIPTION 121 2 - ([(4-fluorophenyl) methoxy) -5- (1-methyl-1 H -pyrazol-4-yl) benzoic acid (D121) 2-. { [(4-Fluorophenyl) methyl] oxi} -5- (1-methyl-1 H-pyrazol-4-yl) benzoate (4-fluorophenyl) methyl (can be prepared as described in description 120; 360 mg, 0.83 mmol) was dissolved in tetrahydrofuran (20 ml) and water (5 ml). Then LiOH (99 mg, 4.14 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. The solvent was removed. The residue was dissolved in water (20 ml). The solution was acidified with 1 N HCl to pH < 5. The precipitate was filtered, washed with ether and dried under vacuum to give the title compound as a white solid. 260 mg.
LC S: MH + = 326.9 DESCRIPTION 122 2- (R (4-fluorophenyl) methyloxy> -5-r (1Z) -3-oxo-1-propen-1-methylbenzoate (D122) To a suspension of 2-. { [(4-fluorophenyl) methyl] oxy} Methyl iodobenzoate (can be prepared as described in 1 12; 740 mg, 1.92 mmol) in N, N-dimethylformamide (5 mL) was added 3,3-bis (ethyloxy) -1-propene ( 0.88 ml, 5.8 mmol), potassium carbonate (397 mg, 2.87 mmol) and PdOAc2 (25.8 mg, 0.1 15 mmol). The reaction was heated in the microwave at 120 ° C for 40 minutes, cooled and then 2M HCl (5 ml) was added and the mixture was stirred for 20 minutes. The mixture was extracted with diethyl ether (210 mL), the organic layer was dried (MgSO4) and the solvent was removed under vacuum. Purification by column (Si, Isolute, cyclohexane 6: 1 / ethyl acetate) gave the title compound. 163 mg.
MS (electrospray): m / z [M + H] + No mass was seen, but the NMR was consistent with the product.
DESCRIPTION 123 2-f r (4-Fluorophenyl) methyloxy) -5-r (1 Z) -3- (4-morpholinyl) -1-propene-1-methylbenzoate (D123) To a solution of 2-. { [(4-fluorophenyl) methyl] oxy} Methyl [(1Z) -3-oxo-1 -propene-1-ylbenzoate (can be prepared as described in the description 122; 163 mg, 0.52 mmol) in 1,2-dichloroethane (10 ml) is added morpholine (0.05 ml, 0.52 mmole) and acetic acid (0.03 ml, 0.52 mmole). The solution was stirred for 3 hours, sodium triacetoxyborohydride (165 mg, 0.78 mmol) was added and stirred for one hour. Saturated NaHCO 3 solution (10 mL) was added and the mixture was stirred for 15 minutes. Dichloromethane (10 ml) was added and the organic layer was separated, dried (MgSO 4) and the solvent was removed under vacuum to give the title compound as a yellow gum. 197 mg.
MS (electrospray): m / z [M + H] + 386 DESCRIPTION 124 2- (f (4-Fluorophenyl) methyloxy) -5-r3- (4-morpholinyl) propybenzoate methyl (D124) 2-. { [(4-Fluorophenol) methyl] oxy]} -5 - [(127E) -3- (4-morpholinyl) -1-propen-1 -yl] - / V-3-pyridinylbenzamide (can be prepared as described in the description 123; 197 mg, 0.51 mmol) is Redissolved in methanol (10 mL) and added to Pd / C (40 mg, 0.38 mmol). The mixture was placed under a hydrogen atmosphere for 3 hours, filtered through Celite and the solvent removed under vacuum to give the title compound as an oil. 166 mg.
MS (electrospray): m / z [M + H] + 388 EXAMPLE 1 5- (1-Methylethyl) -2-f (phenylmethyl) oxn-N-3-pyridinylbenzamide A solution of 5- (1-methylethyl) -2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in the description 3; 300 mg, 1.1 1 mmol), pyridin-3-amine (157 mg, 1.67 mmol), EDC (319 mg, 1.67 mmol) and HOBT (255 mg, 1665 mmol) DMF (5 ml) was stirred at room temperature atmosphere during the night. The reaction mixture was poured into water (20 ml), filtered and the solid was washed with water and dried to give a white solid. The crude product was purified by silica gel chromatography, eluting with petroleum ether: ethyl acetate (3: 1) to give the title compound as a white solid. 140 mg.
MS (electrospray): m / z [M + H] + = 347 1 H NMR (DMSO-d 6): 1.21 (6 H, d, J = 7.2 Hz), 2.93 (1 H, m), 5.23 (2 H, s), 7.21 -7.23 (1 H, d, J = 3.2, J = 8.8 Hz), 7.33-7.42 (5H, m), 7.52-7.56 (3H, m), 8.10 (1 H, d, J = 8.8 Hz), 8.27 (1 H, dd, J = 1.2 Hz J = 4.8 Hz ), 8.67 (1 H, d, J = 2.4 Hz), 10.35 (1 H, s).
EXAMPLE 2 5-Bromo-2-f (phenylmethyl) oxy1-N-3-pyridinylbenzamide (E2) 3-Pyridinamine (123 mg, 1.30 mmol) in DCM (5 mL) was added to a stirred solution of 5-bromo-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 5, method A, 200 mg, 0.65 mmol), HOBT (150 mg, 0.98 mmol) and EDC (187 mg, 0.98 mmol) in DCM (5 ml) under nitrogen at room temperature. The reaction mixture was stirred at 20 ° C overnight. The reaction mixture was partitioned between DCM (50 ml) and water (25 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate and evaporated under vacuum to give the crude product as a yellow solid. The crude product was added to a Biotage column and eluted with petroleum ether: ethyl acetate (3: 1) to give the title compound as a white solid. 75 mg.
MS (electrospray): m / z [M + H] + = 383 1 H NMR (D SO-d 6): 5.25 (2H, s), 7.28 (1 H, d, J = 8.8 Hz), 7.33-7.39 (4H, m), 7.51 (2H, m), 7.71 (1 H, dd, J = 8.8 Hz, J = 2.4 Hz), 7.79 (1 H, d, J = 2.4 Hz), 8.09 (1 H, m), 8.30 (1 H, dd, J = 4.8 Hz, J = 1.6 Hz ), 8.70 (1 H, d, J = 2.4 Hz), 10.44 (1 H, s).
EXAMPLE 3 5- (Methyloxy) -2-f (phenylmethyl) oxy-N-3-pyridinylbenzamide (E3) A solution of 5- (methyloxy) -2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in the description 7; 280 mg, 1.08 mmol), 3-pyridinamine (204 mg, 2.17 mmol), EDC (312 mg, 1.63 mmol) and HOBT (249 mg, 1626 mmol) in DMF (5 mL) was stirred under nitrogen at 25 ° C overnight. The reaction mixture was then poured into water (20 ml), filtered and the solid was washed with water and dried to give the title compound as a white solid. 150 mg.
MS (electrospray): m / z [M + H] = 335 1 H NMR (DMSO-d 6): 3.83 (3H, s), 5.26 (2H, s), 7.16 (1 H, dd, J = 2.8 Hz, J = 8.8 Hz), 7.29-7.33 (2H, m), 7.38. -7.44 (4H, m), 7.56-7.58 (2H, d, J = 6.4 Hz), 8.14 (1 H, d, J = 8.8 Hz), 8.33 (1 H, dd, 1.2 Hz, J = 4.8 Hz) , 8.71 (1 H, d, J = 2.0 Hz), 10.44 (1 H, s).
EXAMPLE 4 5-Methyl-2-r (phenylmethyl) oxy-N-3-pyridinylbenzamide (E4) A solution of 5-methyl-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in the description 9; 400 mg, 1.65 mmol), 3-pyridinamine (31 1 mg, 3.30 mmol), HOBT ( 379 mg, 2.48 mmol) and EDC (475 mg, 2.48 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (20 ml), filtered and the solid was washed with water and dried to give the title compound as a white solid. 220 mg.
MS (electrospray): m / z [M + H] + = 3 9 1 H NMR (DMS0-d 6): 2.30 (3H, s), 5.22 (2H, s), 7.18-7.20 (1 H, d, J = 8.4 Hz), 7.31-7.39 (5H, m), 7.52-7.54 ( 3H, m), 8.09 (1 H, m), 8.27 (1 H, dd, J = 4.8 Hz, J = 1.2 Hz), 8.66 (1 H, d, J = 2.4 Hz), 10.34 (1H, s) .
EXAMPLE 5 5-Bromo-A - (3-methylphenyl) -2-phenylmethyl) oxnbenzamide (E5) Solid 5-bromo-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 5, method B, 200 mg, 0.651 mmol) was added to a stirred suspension of CDI (106 mg, 0.651 mmol) ) in THF (6 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at room temperature for 10 min and m-toluidine (69.8 mg, 0.65 mmol) was added dropwise. After refluxing for 14 hr, the reaction mixture was concentrated to obtain crude product. The crude product was dissolved in 20 ml of CH 2 Cl 2 and the organic phase was washed with 2M hydrochloric acid (5 ml), water (5 ml), dried over sodium sulfate and evaporated under vacuum to give yellow solid. The crude product was further purified by silica gel chromatography eluting with hexane: ethyl acetate (10: 1) to give the title compound. 120 mg.
MS (electrospray): m / z [M + H] + = 396, 398.
EXAMPLE 6 5-Bromo-2-f (phenylmethyl) oxn-N-4-pyridazinylbenzamide (E6) Solid 5-bromo-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 5, method C, 200 mg, 0.651 mmol) was added to a stirred suspension of CDI (106 mg, 0.651 mmol) in THF (10 mL) under nitrogen at 20 ° C. The reaction mixture was stirred at room temperature for 10 min and 4-pyridazinamine (it can be prepared as described in the description 1 1; 61.9 mg, 0.65 mmol) was added dropwise. After refluxing for 14 hr, the reaction mixture was concentrated. Water was added to the residue and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate and evaporated under vacuum. The residue was washed with methanol to give the title compound as a white solid. 95 mg.
MS (electrospray): m / z [M + H] = 384 1 H NMR (DMSO-d 6): 5.29 (2H, s), 7.32-7.40 (4H, m), 7.52 (1 H, s), 7.53 (1 H, s), 7.76 (1 H, dd, J = 2.8 Hz, J = 9.2 Hz), 7.83 (1 H, d, J = 2.8 Hz), 8.05 (1 H, dd, J = 2.4 Hz, J = 6 Hz), 9.1 1 (1 H, d, J = 6 Hz), 9.30 (1 H, d, J = 2.4 Hz), 10.90 (1 H, s) EXAMPLE 7 5-Bromo-A / - (3-chlorophenyl) -2-r (phenylmethyl) oxy-benzamide (E7) Solid 5-bromo-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 5, method B, 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) ) in THF (6 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at room temperature for 10 min. 3-Chlorobenzenamine (83 mg, 0.65 mmol) was then added dropwise. After refluxing for 14 hr, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane: ethyl acetate (10: 1) to give the title compound. 1 10 mg.
MS (electrospray): m / z [M + H] + = 416, 418 EXAMPLE 8 5-Cyano-2-f (phenylmethyl) oxy-N-3-pyridinylbenzamide (E8) A solution of 5-cyano-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 14; 160 mg, 0.63 mmol), 3-pyridinamine (65.4 mg, 0.70 mmol), HOBT (116 mg, 0.76 mmol) and EDC (145 mg, 0.76 mmol) in DMF (10 mL) was stirred at room temperature overnight. Water (30 ml) was added and the mixture was then filtered. The residue was dried to give the title compound as a white solid. 90 mg.
MS (electrospray): m / z, [M + H] + = 330 1 H NMR (DMSO-d 6): 5.31 (2H, s), 7.31 -7.35 (4H, m), 7.42-7.49 (3H, m), 7.97 (1 H, dd, J = 2 Hz, J = 8.4 Hz) , 8.04 (1 H, d, J = 2 Hz), 8.07 (2 H, m), 8.28 (1 H, s), 8.72 (1 H, bs), 10.49 (1 H, s) EXAMPLE 9 5-Bromo-2- (f (4-chlorophenyl) methyloxy> -A / -3-pyridinylbenzamide (E9) Solid pyridine-3-amine (99 mg, 1.05 mmol) was added in a charge to a stirred solution of 5-bromo-2- (4-chlorobenzyloxy) benzoic acid (can be prepared as described in description 16, 180 mg , 0.53 mmoles), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (121 mg, 0.63 mmol) and 1-hydroxybenzotriazole (85 mg, 0.63 mmol) in DMF (15 mL) under nitrogen at 20 ° C. The reaction mixture was stirred at 20 ° C for 16 hr. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3 x 30 ml), dried over sodium sulfate, evaporated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate). ethyl = 1.5: 1) to give the title compound as a white solid. 200 mg.
MS (electrospray): m / z, [M + H] + = 417, 419 1 H NMR (CDCl 3): 5.23 (2H, s), 7.03 (1 H, d, J = 8.8 Hz), 7.25 (1 H, dd, J = 8.4 Hz, J = 4.8 Hz), 7.49 (4H, m) , 7.64 (1 H, dd, J = 8.8 Hz, J = 2.4 Hz), 8.06 (1 H, d, J = 8.4 Hz), 8.25 (1 H, d, J = 2.4 Hz), 8.34 (1 H, d, J = 4.8 Hz), 8.45 (1 H, d, J = 2.4 Hz), 9.81 (1 H, s).
EXAMPLE 10 5-Bromo-2 - [(phenylmethyl) oxyfl-N-3-pyridazinylbenzamide (E10) Solid 5-bromo-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 5, method C, 200 mg, 0.651 mmol) was added to a stirred suspension of CDI (106 mg, 0.651 mmol) ) in THF (6 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at room temperature for 10 min and pyridazin-3-amine (61.9 mg, 0.651 mmol) was added dropwise. After refluxing for 14 hr, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography, eluting with hexane: ethyl acetate (4: 1) to give the title compound. 183 mg.
MS (electrospray): m / z, [M + H] + = 384, 386 EXAMPLE 11 5-Bromo-2- ( { F4- (methyloxy) feninmethyl> oxy) -A / -3-pyridinylbenzamide (E11) Solid pyridine-3-amine (12 mg, 1.19 mmol) was added in a charge to a stirred solution of 5-bromo-2- ( { [4- (methyloxy) phenyl] methyl.} Oxy] benzoic acid (can be prepared as described in description 18; 200 mg, 0.59 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (136 mg, 0.71 mmol) and 1-Hydroxybenzotriazole (96 mg, 0.71 mmol) in DMF (20 mL) under nitrogen at 20 ° C. . The reaction mixture was stirred at 20 ° C for 16 hr. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3 x 30 ml), dried over sodium sulfate, evaporated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate). ethyl = 2: 1) to give the title compound as a white solid. 200 mg.
MS (electrospray): m / z, [M + H] + = 413, 415 EXAMPLE 12 5-Bromo-2-f (phenylmethyl) ??? -? - 3-pyridinylbenzamide (E12) A solution of 5-fluoro-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in the description 20, 180 mg, 0.73 mmol), 3-pyridinamine (68.8 mg, 0.73 mmol), HOBT (134 mg, 0.88 mmol) and EDC (168 mg, 0.88 mmol) in DMF (10 mL) was stirred at room temperature overnight. Water (30 ml) was added and the mixture was filtered. The residue was dried to give the title compound as a white solid. 100 mg.
MS (electrospray): m / z [M + H] + = 323 EXAMPLE 13 5-Bromo-2- (r (3-chlorophenyl) methyl-oxo) -N-3-pyridinylbenzamide (E13) Solid pyridine-3-amine (10 mg, 1.17 mmol) was added in a charge to a stirred solution of 5-bromo-2- acid. { [(3- chlorophenyl) methyl] oxy} benzoic acid (can be prepared as described in description 22; 200 mg, 0.59 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (135 mg, 0.70 mmol) and 1-hydroxybenzotriazole (95 mg, 0.70 mmol) ) in DMF (20 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at 20 ° C for 16 hr. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3 x 30 ml), dried over sodium sulfate, evaporated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate). ethyl = 2: 1) to give the title compound as a white solid. 70 mg.
MS (electrospray): m / z [M + H] + = 417, 419 EXAMPLE 14 5-Bromo-2- (r (4-cyanophenyl) methynoxy) -A / -3-pyridinylbenzamide (E14) Solid pyridine-3-amine (82 mg, 0.873 mmol) was added in a charge to a stirred solution of 5-bromo-2- acid. { [(4-cyanophenyl) methyl] oxy} benzoic acid (can be prepared as described in the description 24; 145 mg, 0.44 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) and 1-hydroxybenzotriazole (70.8 mg, 0.52 mmol) ) in DMF (15 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at 20 ° C for 16 hr. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3 x 30 ml), dried over sodium sulfate, evaporated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate). ethyl = 2: 1) to give the title compound as a white solid. 100 mg.
MS (electrospray): m / z [M + H] + = 408, 410 EXAMPLE 15 5-Bromo-2- (f (3-cyanophenyl) methyl-oxo) -A- -3-pyridinylbenzamide (E15) Solid pyridine-3-amine (13 mg, 1.20 mmol) was added in a charge to a stirred solution of 5-bromo-2- acid. { [(3-cyanophenyl) methyl] oxy} benzoic acid (can be prepared as described in description 26; 200 mg, 0.60 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (139 mg, 0.72 mmol) and 1-hydroxybenzotriazole (98 mg, 0.72 mmol) ) in DMF (20 ml) under nitrogen at 20 ° C. The reaction mixture is stirred at 20 ° C for 16 hr. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3 x 30 ml), dried over sodium sulfate, evaporated under vacuum and purified by column chromatography (petroleum ether. ethyl = 2: 1) to give the title compound as a white solid. 170 mg.
MS (electrospray): m / z [M + H] + = 408, 410 EXAMPLE 16 5-Bromo-2- (f (2-chlorophenyl) methyloxy> - / V-3-pyridinylbenzamide (E16) Solid pyridine-3-amine (212 mg, 2.25 mmol) was added in a charge to a stirred solution of 5-bromo-2- acid. { [(2-chlorophenyl) methyl] oxy} benzoic acid (can be prepared as described in description 28; 350 mg, 1.03 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (236 mg, 1.2 mmoles) and 1-hydroxybenzotriazole (166 mg, 1.23 mmoles) in DMF (20 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at 20 ° C for 16 hr. Water (50 ml) was added to the mixture and the mixture was filtered to give the title compound as a white solid. 400 mg.
MS (electrospray): m / z [M + H] + = 417, 419, 421 EXAMPLE 17 5-Bromo- / V-f3- (methyloxy) fenin-2 - [(phenylmethyl) oxnbenzamide (E17) Solid 5-bromo-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 5, method B, 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) ) in THF (6 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at room temperature for 10 min and 3-methoxybenzenamine (80 mg, 0.65 mmol) was added dropwise. After refluxing for 1 hr, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane: ethyl acetate (10: 1). The crude product was added to a column of silica gel and eluted with DC: hexane (2: 1). The crude product was then added to a preparative HPLC column and eluted with 0.05% trifluoroacetic acid, water / acetonitrile to give the title compound. 1 10 mg.
MS (electrospray): m / z [M + H] + = 412, 414 EXAMPLE 18 5-Bromo-2- (. {Fmethyloxy) phenylmethyl) oxy) - ^ - 3-pyridinylbenzamide (E18) Solid pyridin-3-amino (154 mg, 1.63 mmol) was added in a charge to a stirred solution of 5-bromo-2- ( { [3- (methyloxy) phenyl] methyl.}. oxy) benzoic acid (can be prepared as described in the description 30; 275 mg, 0.82 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (188 mg, 0.98 mmol) and 1-hydroxybenzotriazole (132 mg, 0.98 mmole) in DMF (20 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at 20 ° C for 16 hr. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3 x 30 ml), dried over sodium sulfate, evaporated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate). ethyl = 2: 1) to give the title compound as a white solid. 270 mg.
MS (electrospray): m / z [M + H] + = 413, 415 EXAMPLE 19 5-Bromo-AM3-fluorophenyl) -2-f (phenylmethyl) oxflbenzamide (E19) Solid 5-bromo-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 5, method C, 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) ) in THF (6 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at room temperature for 10 min and 3-fluorobenzenamine (72.4 mg, 0.65 mmol) was added dropwise. After refluxing for 14 hr, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane: ethyl acetate (10: 1). The product was then purified by preparative HPLC (A: 0.05% trifluoroacetic acid / water B: dichloromethane) to give the title compound. 73 mg.
E (electroaspersion): m / z [M + H] + = 400, 402; MNa * = 422, 424 EXAMPLE 20 5-Bromo- / V- (3-ethylphenyl) -2-r (phenylmethyl) oxnbenzamide (E20) Solid 5-bromo-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 5, method B, 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) ) in THF (6 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at room temperature for 10 min and 3-ethylbenzenamine (79 mg, 0.65 mmol) was added dropwise. After refluxing for 14 hr, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane: ethyl acetate (10: 1) to give the title compound. 80 mg.
MS (electrospray): m / z [M + H] + = 410, 412 EXAMPLE 21 5-Bromo-2 - ((r2- (methyloxy) phenylmethyl) oxy) -A3-pyridinylbenzamide (E21) Solid pyridine-3-amine (156 mg, 1.66 mmol) was added in a charge to a stirred solution of 5-bromo-2- ( { [2- (methyloxy) phenyl] methyl.}. Oxy) benzoic acid ( it can be prepared as described in the description 32; 280 mg, 0.83 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (191 mg, 1.00 mmol) and 1-hydroxybenzotriazole (135 mg, 1.00 mmol) in DMF (20 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at 20 ° C for 16 hr. The organic phase was washed with water (25 ml), extracted with ethyl acetate (3 x 30 ml), dried over sodium sulfate, evaporated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate). ethyl = 2: 1) to give the title compound as a white solid. 270 mg.
MS (electrospray): m / z [M + H] + = 413, 415 EXAMPLE 22 5-Bromo-2-f (phenylmethyl) oxy1- / V-2-pyridinylbenzamide (E22) Net triethylamine (0.27 ml, 1.95 mmol) and pyridin-2-amine (61.3 mg, 0.65 mmol) were added to a stirred suspension of 5-bromo-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 5, method C, 200 mg, 0.65 mmole), EDC (250 mg, 1.30 mmole) and HOBT (199 mg, 1.30 mmole) in DMF (3 ml) at 20 ° C. The reaction mixture was stirred at 20 ° C overnight and then emptied into 15 ml of water and filtered. The residue was washed with methanol (10 mL) to give the title compound. The stock solution was evaporated and the solid was purified by preparative HPLC, (A: 10 mmole of ammonium carbonate / water B: acetonitrile) to give the title compound. The two batches of product were mixed. 47 mg.
MS (electrospray): m / z [M + H] + = 383, 385 EXAMPLE 23 5-Bromo-2 - ([(2-cyanophenyl) methyloxy.} - V-3-pyridinylbenzamide (E23) Solid pyridine-3-amino (91 mg, 0.96 mmol) was added in a charge to a stirred solution of 5-bromo-2- acid. { [(2-cyanophenyl) methyl] oxy} benzoic acid (can be prepared as described in description 34; 160 mg, 0.48 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (111 mg, 0.58 mmol) and 1-hydroxybenzotriazole (78 mg, 0.58 mmol) ) in DMF (15 ml) under nitrogen at 20 ° C. The reaction mixture was stirred at 20 ° C for 16 hr. The organic phase was washed with water (25 ml) and extracted with ethyl acetate (3 x 30 ml), dried over sodium sulfate, evaporated under vacuum and purified by column chromatography (petroleum ether: ethyl acetate). ethyl = 2: 1) to give the title compound as a white solid. 180 mg.
MS (electroaspersion): m / z [M + H] + = 408, 410 EXAMPLE 24 5-Bromo-2-r (phenylmethyl) oxy1-A / -5-pyrimidinylbenzamide (E24) Solid 5-bromo-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 5, method C, 200 mg, 0.65 mmol) was added to a stirred suspension of CDI (106 mg, 0.65 mmol) ) in THF (3 mL) under nitrogen at 20 ° C. The reaction mixture was stirred at room temperature for 10 min and pyrimidin-5-amine (61.9 mg, 0.65 mmol) was added dropwise. After refluxing for 14 hr, the reaction mixture was concentrated to obtain crude product. The crude product was purified by silica gel chromatography eluting with hexane. ethyl acetate: triethylamine (4: 1: 0.01) to give the title compound. 150 mg.
MS (electrospray): m / z [M + H] + = 384, 386 EXAMPLE 25 Acid { 3-f ((5-chloro-2-r (phenylmethyl) oxphenyl) carbonyl) amino1phenyl > acetic A mix of . { 3 - [(. {5-Chloro-2 - [(phenylmethyl) oxy] phenyl} carbonyl) amino] phenyl-acetic acid methyl ester (can be prepared as described in description 46, 160 mg, 0.39 mmol), HCl 2M (3 mL) and acetic acid (3 mL) was heated at 90 ° C for 4 hours and then cooled to room temperature. Water was added and the mixture was filtered to give a white solid. The crude product was purified by MDAP to give the title compound as a white solid. 53 mg.
MS (electrospray): m / z [M + H] + = 396, 398 EXAMPLE 26 5-Chloro-2 - [(phenylmethyl) oxy-N-3-pyridinylbenzamide (E26) This compound is commercially available.
EXAMPLE 27 5-Bromo-V- (3-r (methylamino) carbonyl-1-phenyl) -2-r (phenylmethyl) oxy-T-benzamide This compound is commercially available.
EXAMPLE 28 5-Bromo-2 - [(1-phenylethyl) oxyl-A-3-pyridinylbenzamide (E28) The compound 5-bromo-2-hydroxy-N-3-pyridinylbenzamide (can be prepared as described in the description 35, 300 mg, 1.02 mmol) was added to a solution of potassium hydroxide (57.4 mg, 1.02 mmol) in methanol (2 ml, 49.4 mmol). The mixture was then stirred at room temperature for 15 min and the solvent was removed under vacuum. To the potassium salt was added DMF (10 ml) and (l-bromoethyl) benzene (189 mg, 1023 mmol). The reaction mixture was then heated under reflux for 2 hr. The mixture was cooled, diluted with water (20 ml) and the precipitate was collected, and finally crystallized from ethyl acetate to give the title compound. 63 mg.
MS (electrospray): m / z [M + H] + = 397, 399 EXAMPLE 28A 5-Bromo-2- (r (1 S) -1-phenylethyloxy) -N-3-pyridinylbenzamide (E28A) To a solution of 5-bromo-2-. { [(1 S) -1-phenylethyl] oxy} Methyl benzoate (can be prepared as described in the description 99; 100 mg, 0.30 mmol) in THF (2 ml) was added potassium trimethylsilanolate (15 mg, 0.90 mmol). The mixture was stirred for 45 minutes. The solvent was removed and the residue redissolved in DMF (2 mL). To the solution was added DIPEA (0.13 ml, 0.75 mmol), 3-aminopyridine (56 mg, 0.60 mmol) and HATU (170 mg, 0.45 mmol). The solution was stirred for 18 hours. The solvent was removed under vacuum and purified by MDAP to give the title example as a colorless gum. 73 mg.
EM (electroaspersion): m / z [M + H] + = 397/399 H NMR (DMSO-de): 1.58 (3 H, d, J = 6.36 Hz), 5.63 (1 H, q, J = 6.21 Hz), 7.00 (1 H, d, J = 8.99 Hz), 7.14-7.62. { 8 H, m), 7.73 (1 H, d, J = 2.63 Hz), 8.10-8.25 (1 H, m), 8.33 (1 H, dd, J = 4.60, 1.32 Hz), 8.84 (1 H, d) , J = 2.19 Hz), 10.46 (1 H, s) EXAMPLE 28B 5-Bromo-2- (r (1 R) -1-phenylenyloxy) -N-3-pyridinylbenzamide (E28B) 5-Bromo-2-hydroxy-N-3-pyridinylbenzamide (can be prepared as described in the description 35; 300 mg, 1023 mmole) was added to a solution of KOH (57.4 mg, 1.02 mmol) in methanol (2 ml, 49.4 mmol). The mixture was then stirred at room temperature for 15 min and the solvent was removed under vacuum. To the potassium salt was added N, N-dimethylformamide (10 ml) and (l-bromoethyl) benzene (189 mg, 1.02 mmol). The reaction mixture was then heated at 80 ° C for 2 hr. The mixture was cooled, diluted with water (20 ml) and the precipitate was collected. Recrystallization from ethyl acetate gave the racemic compound (63 mg). The racemic material was chirally resolved (ChiralPak IA 250mm x 4.6mm, heptane / ethanol (70/30)) to give the title compound. 9 mg.
MS (efectrospray): m / z [M + H] + = 397/399 1 H NMR (DMSO-d 6): 1.58 (3 H, d, J = 6.36 Hz), 5.63 (1 H, q, J = 6.14 Hz), 7.00 (1 H, d, J = 8.99 Hz), 7.20-7.48 (6 H, m), 7.54 (1 H, dd, J = 8.99, 2.63 Hz), 7.73 (1 H, d, J = 2.41 Hz), 8.07-8.25 (1 H, m), 8.33 (1 H, dd, J = 4.71, 1.43 Hz), 8.84 (1 H, d, J = 2.19 Hz), 10.46 (1 H, s) EXAMPLE 29 5-Hydroxy-2-r (phenylmethyl) oxy-N-3-pyridinylbenzamide (E29) HOBT solid (552 mg, 3.60 mmol) was added in a charge to a stirred solution of 5-hydroxy-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in the description 38; 800 mg, 3.28 mmol ), 3-pyridinamine (339 mg, 3.60 mmol) and EDC (691 mg, 3.60 mmol) in DMF (30 ml) at room temperature. The reaction mixture was stirred at room temperature for 4 hr. After 4 hr, water was added to the reaction mixture. The reaction mixture was filtered and the residue was washed with ethyl acetate to give the title compound as a white solid. 500 mg.
MS (electrospray): m / z [M + H] + = 321 H NMR (DMSO-d6). 5.17 (2H, s), 6.91 (1 H, dd, J = 3.2 Hz, J = 9.2 Hz), 7.14 (1 H, d, J = 4.4 Hz), 7.16 (1 H, s), 7.34 (4H, m), 7.51 (2H, dd, J = 1.6 Hz, J = 8.0 Hz), 8.04 (1 H, d, J = 5.2 Hz), 8.25 (1 H, dd, J = 1.6 Hz, J = 5.2 Hz) , 8.6 (1 H, d, J = 2.4 Hz), 9.38 (1 H, s), 10.33 (1 H, s) Method B 3-Pyridinamine (2.20 g, 23.42 mmol) was added to a stirred solution of 5-hydroxy-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in the description 76; 5.2 g, 21.29 mmol), HOBT (3.59 g, 23.4 mmoles) and EDC (4.49 g, 23.42 mmoles) in dimethylformamide (100 ml) at room temperature. The reaction mixture was stirred at 25 ° C overnight. Water was added, the solid was filtered and washed with ethyl acetate to give the title compound as a white solid. 3.7 g.
MS (electrospray): m / z [M + H] + = 321.3.
Method C Oxalyl chloride (1.08 ml, 2.28 mmol) was added to a mixture of 5-hydroxy-2 - [(phenylmethyl) oxy] benzoic acid (1 g, 4.09 mmol) dissolved in dichloromethane. The mixture was stirred for 2 hr and then concentrated. The residue was dissolved in dichloromethane, and then added to a mixture of pyridin-3-amine (0.39 g, 4.09 mmol) and triethylamine (1.14 mL, 8.19 mmol) in dichloromethane. The mixture was stirred at 40 ° C for 3 h. The mixture was filtered and the filtrate was added to water (10 mL) and extracted with ethyl acetate (30 mL). The organic phase was concentrated to give the title compound a crude solid product. 0.72 g.
MS (electrospray): m / z [M + H] + = 321 EXAMPLE 30 5- (r2- (Dimethylamino) etinoxi> -2-f (phenylmethyl) oxn-N-3-pyridinylbenzamide (E30) A solution of DIAD (252 mg, 1249 mmol) in toluene (1 mL) was added dropwise to a stirred solution of 5-hydroxy-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in Example 29, 160 mg, 0.50 mmol), 2- (dimethylamino) ethanol (49.0 mg, 0.549 mmol) and Ph3P (328 mg, 1.25 mmol) in toluene (4 mL) under nitrogen at 0 ° C. The reaction mixture was stirred at 115 ° C overnight. The mixture was then cooled and concentrated. The residue was added to water and extracted with ethyl acetate (3 x 60 mL). The organic phase was washed with saturated brine (30 ml), dried over sodium sulfate and evaporated under vacuum to give crude product. The crude product was added to a column of silica gel (40 g) and eluted with a 20: 1 mixture of DCM / methanol (2 I) to give the title compound as a yellow solid. 50 mg.
MS (electrospray): m / z [M + H] + = 392 1 H NMR (CDC): 2.54 (6H, s), 2.97 (2H, t, J = 4.8 Hz), 4.25 (2H, t, J = 4.8 Hz), 5.19 (2H, s), 7.00-7.20 (3H, m), 7.50 (5H, m), 7.85 (1 H, d, J = 3.2 Hz), 7.99 (1 H, s), 8.07 (1 H, d, J = 8 Hz), 8.26 (1 H, d , J = 4.4 Hz), 10.18 (1 H, s) EXAMPLE 31 5 - [(1-ethyl-4-piperidinyl) oxy1-2-f (phenylmethyl) oxn-N-3-pyridinylbenzamide ÍE3U A solution of DIAD (0.30 mL, 1.56 mmol) in toluene (1 mL) was added dropwise to a solution of 5-hydroxy-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in Example 29, 200 mg, 0.624 mmol), 1-methyl-4-p-peridinol (79 mg, 0.687 mmol) and Ph3P (409 mg, 1561 mmol) in toluene under nitrogen at 0 ° C. The reaction mixture was stirred at 1 15 ° C overnight. The mixture was then cooled and concentrated. The residue was added to water and extracted with ethyl acetate (3 x 60 mL). The organic phase was washed with saturated brine (30 mL), dried over sodium sulfate and evaporated under vacuum to give the crude product. The crude product was purified by CCD-Pre (DCM: methanol = 8: 1) to give the title compound as a yellow solid. 36 mg.
MS (electrospray): m / z [M + H] + = 418 1 H RN (CDCl 3): 1.85 (2 H, m), 2.05 (2 H, m), 2.34 (5 H, m), 2.74 (2 H, m), 4.38 (1 H, m), 5.19 (2 H, s), 7.10 (2H, m), 7.19 (1 H, dd, J = 4.4 Hz, J = 8.4 Hz), 7.51 (5H, m), 7.87 (1 H, d, J = 1.6 Hz), 7.98 (1 H, d , J = 2 Hz), 8.10 (1 H, d, J = 8.4 Hz), 8.26 (1 H, d, J = 3.6 Hz), 10.18 (1 H, s) EXAMPLE 32 5- (4-Methyl-1-piperazinyl) -2-f (phenylmethyl) oxn-N-3-pyridinylbenzamide (E32) A solution of 5- (4-methyl-1-piperazinyl) -2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in the description 40; 50 mg, 0.15 mmol), 3-pyridinamine (14.42 mg , 0.15 mmol), EDC (29.4 mg, 0.15 mmol), HOBT (23.46 mg, 0.15 mmol) and triethylamine (0.02 mL, 0.15 mmol) was dissolved in DMF (5 mL) was stirred for 3 hr at 40 ° C. The mixture was then filtered and 10 ml of water added to the filtrate. The mixture was then extracted with ethyl acetate (30 ml) and concentrated. The residue was then purified by reverse phase HPLC using a gradient of acetonitrile and 0.1% aqueous ammonia as the eluent. Evaporation of the product containing fractions gave the title compound as a white solid. 25 mg.
MS (electrospray): m / z [M + H] + = 403 1 H NMR (CDCl 3): 2.40 (3H, s), 2.64 (4H, t, J = 4.8 Hz), 3.26 (4H, t, J = 4.8 Hz), 5.21 (2H, s), 7.12-7.14 (2H, m), 7.21 (1 H, dd, J = 8.4 Hz, J = 4.4 Hz), 7.53 (5H, m), 7.93 (1 H, d, J = 2.8 Hz), 8.00 (1 H, d, J = 2.4 Hz), 8.13 (1 H, d, J = 8.4 Hz), 8.28 (1 H, d, J = 4.4 Hz), 10.21 (1 H, s).
EXAMPLE 33 2-f (Phenylmethyl) oxn-5- (1-piperidinyl) -N-3-pyridinylbenzamide (E33) A solution of 2 - [(phenylmethyl) oxy] -5- (1-piperidinyl) benzoic acid (can be prepared as described in description 42; 80 mg, 0.26 mmol), 3-pyridinamine (24.18 mg, 0.26 mmol) , EDC (49.3 mg, 0.26 mmol), HOBT (39.3 mg, 0.26 mmol) and triethylamine (0.04 ml), 0.26 mmole) in DMF (5 ml) was stirred for 3 hr at 40 ° C. The mixture was then filtered and 10 ml of water was added to the filtrate. The mixture was extracted with ethyl acetate (30 ml) and concentrated. The residue was then purified by reverse phase HPLC using a gradient of acetonitrile and 0.1% aqueous trifluoroacetic acid as the eluent. Evaporation of the product containing fractions gave the trifluoroacetate salt of the title compound as a light yellow solid. , 48 mg. 1 H NMR (DMSO-d 6) MS (electrospray): m / z [M + H] + = 388 The trifluoroacetate salt was dissolved in water. 1N NaHCO3 solution was added and the mixture was extracted three times with ethyl acetate. The organic phase was concentrated to give the title compound. 26 mg. 1 H NMR (DMSO-d 6) MS (electrospray): m / z [M + H] + = 388 H NMR (DMSO-d6): 1.53 (2H, m), 1.64 (4H, m), 3.07 (4H, m), 5.19 (2H, s), 7.15 (2H, m), 7.27 (1H, d, J = 2.8 Hz), 7.37 (4H, m), 7.52 (2H, d, J = 6.8 Hz), 8.08 (1 H, d, J = 8.4 Hz), 8.27 (1 H, d, J = 4.4 Hz) , 8.65 (1 H, d, J = 3.6 Hz), 10.35 (1 H, s).
EXAMPLE 34 5-Bromo-N-1, 3-oxazol-2-yl-2-f (phenylmethyl) oxy-1-benzamide (E34) Solid 5-bromo-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in the description 5; 200 mg, 0.65 mmole) was added to a stirred suspension of CDI (106 mg, 0.65 mmole) in tetrahydrofuran (10 mL) under nitrogen at 20 ° C. The reaction mixture was stirred at room temperature for 10 min. 1,3-Oxazol-2-amine (54.7 mg, 0.65 mmol) was then added and the reaction mixture was refluxed overnight. The reaction mixture was concentrated. Water (100 ml) was added to the residue followed by extraction with ethyl acetate (3 x 50 ml). The combined organic phase was washed with saturated brine (25 ml), dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by thin layer chromatography (petroleum ether: ethyl acetate = 2: 1) followed by CLAR-Prep (Gilson GX-281; Shimazu 15 pM; 250 * 19 mm; A: 10 mmole NH4HC03 / water , B: CH 3 CN 0-9 min, 70-80%, 9-9.3 min, 80-95%, 9.3-13 min, 95% CH 3 CN, RT: 8.0min) to give the title compound as a white solid. 15 mg. 1 H NMR (400 MHz, CDCl 3): 5.31 (s, 2 H), 6.90 (d, J = 8.8 Hz, 1 H), .02 (s, H), 7.42-7.46 (m, 6 H), 8.42 (d, J = 2.8 Hz, 1 H), 10.51 (s, 1 H) MS (electrospray): m / z [M + H] + = 373 EXAMPLE 35 5-f (4-Methyl-1-piperazinH) carbonyl1-2-f (phenylmethyl) oxn-N-3-pyridinylbenzam ÍE35J To a solution of 5 - [(4-methyl-1-piperazinyl) carbonyl] -2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 51; 166 mg, 0.47 mmol), 3-pyridineamine (44.1 mg, 0.47 mmole), and EDC (90 mg, 0.47 mmole) in?,? - dimethylformamide (DMF) (4 mL) stirred under nitrogen at room temperature was added net HOBT (71.7 mg, 0.47 mmoles) in a load. The reaction mixture was stirred at room temperature for 6 hr. The mixture was diluted with water (50 ml), extracted with ethyl acetate (3 x 50 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate and evaporated under vacuum to give the crude product. The crude product was purified by CLAR-Prep (Gilson GX-281, Durashell 10 pm, 21.5 * 250 mm, A: 10 mmol / water, B: MeCN, 0-7.2 min, 35% - 35%; 7.2-7.5 min, 35% -95%; 7.5-11.5 min, 95%; RT: 7.0 min) to give the title compound as a white solid. 30 mg.
H NMR (400 MHz, CDCl 3): 2.34 (m, 4 H), 3.55-3.80 (m, 4 H), 5.28 (s, 2 H), 7.19-7.21 (t, J = 4.8 Hz, 1 H), 7.23 (d , J = 8.8 Hz, 1 H), 7.53-7.55 (m, 5H), 7.70-7.73 (dd, J = 2.4 Hz, J = 9.0 Hz, 1 H) 7.94 (s, 1 H), 8.13 (m, 1 H), 8.28 (m, 1 H), 8.37 (d, J = 2.4 Hz, 1 H), 9.98 (s, 1 H) MS (electrospray): m / z [M + H] + = 431 EXAMPLE 36 2-((Phenylmethyl) oxy-5- (1-piperidinylcarbonyl) -N-3-pyridinylbenzamide (E36) Net HOBT (90 mg, 0.59 mmole) was added in a charge to a stirred solution of 2 - [(phenylmethyl) oxy] -5- (1-piperidinylcarbonyl) benzoic acid (can be prepared as described in description 53; mg, 0.59 mmol), 3-pyridinamine (55.5 mg, 0.59 mmol), and EDC (13 mg, 0.59 mmol) in N, N-dimethylformamide (5 mL) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 4 hr. The mixture was diluted with water (50 ml). The precipitate was collected by Filtration was washed with ether (5 ml) and dried to give the title compound as a white solid. 65 mg. 1 H NMR (400 MHz, CDCl 3): 1.61 (m, 4 H), 1.70 (m, 2 H), 3.14-3.72 (m, 2 H), 5.28 (s, 1 H), 7.19-7.22 (m, 2 H), 7.52. -7.55 (m, 5H), 7.68-7.71 (m, 1 H), 7.97 (s, 1 H), 8.1 1-8.14 (m, 1 H), 8.28 (d, J = 3.6 Hz, H), 8.36 (d, J = 2.0 Hz, 1 H), 10.00 (s, 1 H) MS (electrospray): m / z [M + H] + = 416 EXAMPLE 37 2-r (Phenylmethyl) oxy-N-3-pyridinyl-5- (1-pyrrolidinylcarbonyl) benzamide (E37) Net HOBT (94 mg, 0.62 mmol) was added in a charge to a stirred solution of 2- [. { phenylmethyl) oxy] -5- (1-pyrrolidinylcarbonyl) benzoic acid (can be prepared as described in the description 55; 200 mg, 0.62 mmol), 3-pyridinamine (57.9 mg, 0.62 mmol and EDC (1 18 mg, 0.62 mmol) ) in N, N-dimethylformamide (5 ml) under nitrogen at room temperature The reaction mixture was stirred at room temperature for 4 h The mixture was diluted with water (50 ml) The precipitate was collected by filtration, washed with ether (5 ml) and dried to give the title compound as a white solid, 88 mg.
H NMR (400 MHz, CDCl 3): 1.90-1.99 (m, 4H), 3.53-3.68 (m, 4H), 5.28 (s, 1 H), 7.19-7.22 (m, 2H), 7.51-7.57 (m, 5H), 7.84-7.86 (dd, J = 2.0 Hz, J = 8.4Hz, 1 H), 7.98-7.99 (d, J = 2.8 Hz, 1 H), 8.10-8.1 1 (m, 1 H), 8.28 (d, J = 3.6 Hz, 1 H), 8.52 (d, J = 2.0 Hz, 1 H), 10.00 (s, 1 H) MS (electrospray): m / z [M + H] + = 402 EXAMPLE 38 5- (4-Morpholinylcarbonyl -2-r (phenylmethyl) oxy-N-3-pyridinylbenzamide (E38) Net HOBT (90 mg, 0.59 mimoles) was added in a charge to a stirred solution of 5- (4-morpholinylcarbonyl) -2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in the description 57; 200 mg, 0.59 mmol), 3-pyridinamine (55.1 mg, 0.59 mmol) and EDC (12 mg, 0.59 mmol) in N, N-dimethylformamide (5 mL) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 4 hr. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (3 x 50 ml). The organic phase was washed with sodium hydroxide solution (1 mol / L, 25 mL), saturated brine (25 mL), dried over sodium sulfate and evaporated under vacuum to give the crude product. The crude product was washed with ether (5 mL) and dried to give the title compound as a white solid. 67 mg.
H NMR (400 MHz, CDCl 3): 3.72 (m, 8H), 5.28 (s, 1 H), 7.19-7.25 (m, 2H), 7.52-7.54 (m, 5H), 7.71-7.73 (dd, J = 2.0 Hz, J = 8.4 Hz, 1 H), 7.97 (m, 1 H), 8.1 1-8.13 (m, 1 H), 8.28 (d, J = 3.6 Hz, 1 H), 8.37 (d, J = 2.0 Hz, 1 H), 9.98 (s, 1 H) MS (electrospray): m / z [M + H] + = 418 EXAMPLE 39 ^ \ ^ 1-Dimethyl-4-r (phenylmethionn- ^ 3-3-pyridinyl-1,3-benzenedicarboxamide ÍI401 HOBT (102 mg, 0.67 mmol) was added in a charge to a stirred solution of 5 - [(dimethylamino) carbonyl] -2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in description 59; 200 mg, 0.67 mmol), 3-pyridinamine (62.9 mg, 0.67 mmol) and EDC (128 mg, 0.67 mg). mmoles) in?,? - dimethylformamide (5 ml) under nitrogen at room temperature. The reaction mixture was stirred at room temperature for 4 hr. The mixture was diluted with water (50 ml). The precipitate was collected by filtration. The solid was dissolved in ethyl acetate (100 ml), and the organic phase was washed with NaOH (1 mol / l 25 ml), water (25 ml), saturated brine (25 ml), dried over sodium sulfate and evaporated under vacuum to give the title compound as a white solid. 78 mg. 1 H NMR (400 MHz, CDCl 3): 3.10 (t, J = 1.0 Hz, J = 6.8 Hz, 6H), 5.28 (s, 1 H), 7.19-7.23 (m, 2H), 7.52-7.55 (m, 5H ), 7.71-7.74 (d, J = 2.0 Hz, J = 8.8 Hz, 1 H), 7.97 (s, 1 H), 8.11-8.12 (m, 1 H), 8.28 (d, J = 3.2 Hz, 1 H), 8.40 (d, J = 2.0 Hz, 1 H), 9.99 (s, 1 H) MS (electrospray): m / z [M + H] + = 376 EXAMPLE 40 5-F (Dimethylamino) sulfonin-2-f (phenylmethyl) oxn-A / -3-pyridinylbenzamide (E40) A solution of oxalyl chloride (0.06 ml, 0.69 mmol) in dichloromethane (5 ml) was added dropwise over 1 minute to a solution 5 - [(d.methylamino) sulfonyl] -2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in the description 63; 230 mg, 0.69 mmol) in dichloromethane (5 ml) at 0 ° C. The reaction mixture was stirred at 25 ° C for 0.5 hr, and then concentrated under reduced pressure to give the crude acyl chloride as a yellow solid. A solution of this crude acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (64.5 mg., 0.69 mmole) and diisopropylethylamine (0.12 ml, 0.69 mmole) in dichloromethane (20 ml) under nitrogen at 0 ° C. The reaction mixture was stirred at 25 ° C for 1 hr. The organic phase was washed with water (25 ml) three times and saturated brine (10 ml) twice, dried over sodium sulfate and evaporated under vacuum to give the crude product as an orange oil. The product was crystallized from methanol to give the title compound as a white solid. 170 mg. MS (electrospray): m / z [M + H] + = 412 1 H NMR (400MHz, DMSO-d 6): 2.64 (6H, s), 5.35 (2H, s), 7.35-7.40 (4H, m), 7.53-7.56 (3H, t), 7.90-7.95 (2H, m) , 8.10 (1 H, d, J = 8.4), 8.30 (1 H, dd, J = 0.8, 1.2), 8.72 (1 H, s), 10.52 (1 H, s) EXAMPLE 41 5- (4-Morpholinylsulfonyl) -2-r (phenylmethyl) oxy-1-V-3-pyridinylbenzamide (E41) A solution of oxalyl chloride (0.06 ml, 0.66 mmol) in dichloromethane (5 ml) was added dropwise over 1 min to a stirred solution of 5- (4-morpholinylsulfonyl) -2 - [(phenylmethyl) oxy] benzoic acid. (can be prepared as described in description 66; 250 mg, 0.66 mmol) in dichloromethane (5 ml) at 0 ° C. The reaction mixture was stirred at 25 ° C for 0.5 hr. The organic phase was evaporated under vacuum to give the crude acyl chloride as a yellow solid. A solution of this crude acyl chloride in dichloromethane (5 mL) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (62.3 mg, 0.66 mmol) and diisopropylethylamine (0.12 mL, 0.66 mmol) in dichloromethane (20 mL). mi) under nitrogen at 0 ° C. The reaction mixture was stirred at 25 ° C for 1 hr. The organic phase was washed with water (25 ml) three times and saturated brine (10 ml) twice, dried over sodium sulfate and evaporated under vacuum to give the crude product as an orange oil. The product was crystallized from methanol to give the title compound as a white solid. 169 mg. 1 H NMR (400 MHz, DMSO-C 6): 2.88-2.90 (4H, t), 3.64-3.67 (4H, t), 5.36 (2H, s), 7.35-7.40 (4H, m), 7.54-7.57 (3H, m), 7.89-7.94 (2H, m), 8.09-8.12 (1 H, m), 8.30-8.32 (1H, m), 8.72 (1 H, d, J = 1.6), 10.53 (1 H, S) MS (electrospray): m / z [M + H] + 453.9 EXAMPLE 42 2 - [(Phenylmethyl) oxn-5 - (- piperidinylsulfonyl) - 3-pyridinylbenzamide (E42) Oxalyl chloride (0.05 ml, 0.59 mmole) in dichloromethane (5 ml) was added dropwise over 1 min to a stirred solution of 2 - [(phenylmethyl) oxy] -5- (1-piperidinylsulfonyl) benzoic acid ( it can be prepared as described in the description 69; 220 mg, 0.59 mmole) in dichloromethane (5 ml) at 0 ° C. The reaction mixture was stirred at 25 ° C for 0.5 hr, and then concentrated under reduced pressure to give crude acyl chloride. A solution of this crude acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (55.1 mg, 0.59 mmole) and diisopropylethylamine (0.10 ml, 0.59 mmole) in dichloromethane (20 ml). ml) under nitrogen at 0 ° C. The reaction mixture was stirred at 25 ° C for 1 hr.
The organic phase was washed with water (25 ml) three times, saturated brine (10 ml) twice, dried over sodium sulfate and evaporated under vacuum to give crude product as an orange oil. The product was crystallized from methanol to give the title compound as a white solid. 125 mg. 1 H NMR (400MHz, DMSO-c / 6): 1.38 (2H, d, J = 4.4), 1.56 (4H, d, J = 4.4), 2.89-2.92 (4H, t), 5.34 (2H, s), 7.34-7.41 (4H, m), 7.53-7.56 (3H, m), 7.87-7.93 (2H, m), 8.09-8.11 (1H, t), 8.31 (1H, s), 8.72 (1H, s), 10.50 (1 H, s) MS (electrospray): m / z [M + H] + = 451.9 EXAMPLE 43 5-f (4-Methyl-1-piperazinyl) sulfonin-2-f (phenylmethyl) oxy-A / -3-pyridinylbenzamide ÍE43J A solution of oxalyl chloride (0.03 mL, 0.31 mmol) in dichloromethane (5 mL) was added dropwise over 1 min to a stirred solution of 5 - [(4-methyl-1-piperazinyl) sulfonyl] -2- [(phenylmethyl) oxy] benzoic acid (can be prepared as described in the description 72; 120 mg, 0.31 mmol) in dichloromethane (5 ml) at 0 ° C. The reaction mixture was stirred at 25 ° C for 0.5 hr, and then concentrated to give crude acyl chloride. A solution of this acyl chloride in dichloromethane (5 ml) was added dropwise over 5 min to a stirred solution of 3-pyridinamine (28.9 mg, 0.31 mmol) and diisopropylethylamine (0.05 ml, 0.31 mmol) in dichloromethane ( 20 ml) under nitrogen at 0 ° C. The reaction mixture was stirred at 25 ° C for 1 hr. The organic phase was washed with water (25 ml) three times, saturated brine (10 ml) twice, dried over sodium sulfate and evaporated under vacuum to give crude product as an orange oil. The crude product was crystallized from methanol to give the title compound as a white solid. 30 mg.
H NMR (400MHz, DMSO-d6): 2.15 (3H, s), 2.38 (4H, d, J = 4.4), 2.91 (4H, s), 5.36 (2H, s), 7.34-7.40 (4H, m) , 7.53-7.55 (3H, d, J = 8.8), 7.87-7.93 (2H, m), 8.08-8.1 (1 H, m), 8.30-8.32 (1 H, m), 8.72 (1 H, d, J = 1.6), 10.51 (1 H, s) MS (electrospray): m / z [M + H] + = 467 EXAMPLE 44 2-r (Phenylmethyl) oxy-1-V-3-pyridinyl-5. { r (2R) -2-pyrrolidinylmethyloxy > benzamide (E441 Trifluoroacetic acid (1.5 ml, 19.47 mmol) was added dropwise to an ice-cooled solution of (2F?) - 2 - [(. {4 - [(phenylmethyl) oxy] -3 - [(3-pyridinylamino ) carbonyl] phenyl.} oxy] methyl] -1-pyrrolidinecarboxylate 1,1-dimethylethyl ester (can be prepared as described in the description 73; 500 mg, 0.99 mmol) in dichloromethane (15 ml). After stirring at 25 ° C for 2 hr, the pH of the solution was adjusted to 7-8 by the addition of aqueous NaHCO 3 solution. The mixture was extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over Na2SO4 and concentrated to obtain a crude product. Half of the crude product was purified by pre-HPLC (Gilson GX-281, Waters X-Bridge 5 μ? T ?, 100 * 19 mm; A: 0.04% NH3.H20 / water, B: CH3CN; 0-7 min, 35% -50%, 7-14 min, 95%, RT = 6.5 min) to give the title compound as a light yellow solid. 70 mg. 1 H NMR (400 MHz. CDCl 3): 10.20 (s, 1 H), 8.27 (dd, 1 H), 8.12 (d, 1 H), 8.00 (t, 1 H), 7.53 (m, 5 H), 7.20 ( m, H), 7.12 (m, 2H), 5.20 (s, 2H), .02 (m, 1 H), 3.91 (m, 1 H), 3.55 (m, 1 H), 3.03 (m, 2H) , 1.96 (m, 1 H), 1.84 (m, H), 1.57 (m, 1 H).
EM (electro-spray): m / z [M + H] + = 404.2.
EXAMPLE 45 5 - ((r (2R) -1-Methyl-2-pyrrolidinylmethyl) oxy) -2-r (phenylmethyl) oxy-Af-3-pyridinylbenzamide (E45) 2 - [(Phenylmethyl) oxy] -N-3-pyridinyl-5. { [(2R) -2-pyrrolidinylmethyl] oxy} Benzamide (can be prepared as described in example 44; 250 mg, 0.62 mmol) was added to formic acid (4.5 ml) at 5 ° C, followed by 40% aqueous formaldehyde (2.4 ml). When the initial evolution of carbon dioxide had disappeared, the mixture was refluxed for 2 hr. After the solution was cooled, the pH of the solution was adjusted to 7-8 by the addition of aqueous NaHCO 3 solution. The mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4 and concentrated to obtain a crude product, which was purified by prep-HPLC to give the title compound as a white solid. 47 mg.
H NMR (400 MHz. CDCl 3): d: 10.20 (s, 1 H), 8.27 (dd, 1 H), 8.12 (d, 1 H), 8.00 (t, 1 H), 7.53 (m, 5H), 7.20 (m, 1 H), 7.12 (m, 2H), 5.20 (s, 2H), 4.02 (m, 1 H), 3.91 (m, 1 H), 3.55 (m, 1 H), 3.03 ( m, 2H), 2.37 (s, 3H), 1.96 (m, 1 H), 1.84 (m, 2H), 1.57 (m, 1 H).
MS (electrospray): m / z [M + H] + = 418.2.
EXAMPLE 46 2-r (Phenylmethyl) oxy1-A / -3-pyridinyl-5- (r (2S) -2-pyrrolidinylmethylloxy) benzam ÍE46J To an ice-cooled solution of (2S) -2 - [(. {4 - [(phenylmethyl) oxy] -3 - [(3-pyridinylamino) carbonyl] phenyl] yl) oxy] methyl] -1-pyrrolidinecarboxylate of 1-dimethylethyl (can be prepared as described in the description 74; 0.6 g, 1 19 mmol) in dichloromethane (15 ml) was added trifluoroacetic acid (2.0 ml, 26 mmol) dropwise. After being stirred at 25 ° C for 2 hr, the pH of the solution was adjusted to 7-8 by the addition of aqueous NaHCO 3 solution. The mixture was extracted with dichloromethane. The dichloromethane layer was washed with brine, dried over Na 2 SO 4 and concentrated to obtain a crude product. He crude product was purified by prep-HPLC (Gilson GX-281, Waters X-Bridge 5 μ? - ?, 100 * 19 mm; A: 0.04% NH3.H20 / water, B: CH3CN¡0-7 min, 35% -50%; 7-14 min, 95% RT = 7.0 min) to give the title compound as a light yellow solid. 150 mg.
H NMR (400MHz, CDCl 3): 1.57 (m, 1 H), 1.81 (m, 2H), 1.97 (m, 1 H), 3.00 (m, 2H), 3.53 (m, 1 H), 3.91 (m, 1 H), 4.02 (m, 1 H), 5.20 (s, 2H), 7.1 1-7.16 (m, 2H), 7.21 (m, 1 H), 7.52 (m, 5H), 7.86 (s, 1 H) ), 8.00 (s, 1 H), 8.12 (m, 1 H), 8.28 (d, J = 4 Hz, 1 H), 10.20 (s, 1 H) MS (electrospray): m / z [M + H] + = 404.3 EXAMPLE 47 5 ((r (2S) -1-Methyl-2-pyrrolidininmethyl) oxy-2-r (phenylmethyl) oxyl-A / -3-pyridinylbenzamide (E47) 2 - [(Phenylmethyl) oxy] - / \ / - 3-pyridinyl-5-. { [(2S) -2-pyrrolidinylmethyl] oxy} Benzamide (can be prepared as described in Example 46; 80 mg, 0.20 mmol) was added to formic acid (4 mL) at 5 ° C, followed by aqueous formaldehyde (40%, 2.0 mL). When the initial evolution of carbon dioxide had disappeared, the mixture was refluxed for 2 hr. After the solution was cooled, the pH of the solution was adjusted to 7-8 by the addition of aqueous NaHCOa solution. The mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4 and concentrated to obtain a crude product. The crude product was purified by prep-HPLC (Gilson GX-281, Waters X-Bridge 5 μp ?, 100 * 19 mm; A: 0.04% NH3.H20 / water, B: CH3CN¡0-7.2 min, 40% - 50%; 7.2-7.5 min, 50% -95% 7.5-11.5 min, 95%, RT = 4.0 min) to give the title compound as a white solid. 68 mg. 1 H NMR (CDCl 3, 400 MHz): 1.77-1.91 (m, 3 H), 2.04-2.09 (m, 1 H), 2.36 (m, 1 H), 2.54 (s, 3 H), 2.73 (m, 1 H) , 3.18 (t, 1 H), 4.00-4.11 (m, 2H), 5.21 (s, 2H), 7.1 1 -7.16 (m, 2H), 7.21 (m, 1 H), 7.54 (m, 5H), 7.88 (d, J = 2.4 Hz, 1 H), 7.98 (d, J = 2.4 Hz, H), 8.13 (m, 1 H), 8.28 (d, J = 4 Hz, 1 H), 10.25 (s, 1 HOUR) EM (electroaspersion): m / z [M + H] + = 418.2 EXAMPLE 48 5-. { r2- (Methylamino) etinoxy) -2-f (phenylmethyl) oxn-A / -3-pyridinylbenzamide (E48) To the solution of 1,1-dimethylethyl methyl [2- (. {4 - ((phenylmethyl) oxy] -3 - [(3-pyridinylamino) carbonyl] phenyl]} oxy] ethyl] carbamate (can be prepared as described in description 75, 140 mg, 0.17 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (3.0 ml, 38.9 mmol) dropwise.After stirring at 30 ° C for 2 hr, the pH of the solution it was adjusted to 7-8 by the addition of aqueous NaHC03 solution The mixture was extracted with dichloromethane The dichloromethane layer was washed with brine, dried over Na2SO4 and concentrated to obtain a crude product The crude product was purified by prep-HPLC (Gilson GX-28, Waters X-Bridge 5 pm, 100 * 30 mm, A: 0.04% NH3.H20 / water, B: CH3CN, 0-6.0 min, 30% -55%, 6-12 min , 95%, RT = 7.3 min) to give the title compound as a white solid 20 mg. 1 H NMR (400 MHz, CDCl 3): 2.57 (s, 3 H), 3.05 (t, 2 H), 4.17 (t, 2 H), 5.21 (s, 2 H), 7.13 (m, 2 H), 7.21 (m, 1 H). , 7.53 (m, 5H), 7.86 (d, J = 2.4 Hz, 1 H), 8.00 (d, J = 2.4 Hz, 1 H), 8.12 (m, 1 H), 8.28 (d, J = 4 Hz , 1 H), 10.19 (s, 1 H) MS (electrospray): m / z [M + H] + = 378.1 EXAMPLE 49 5 - ((2 - [(2-Aminoethyl) oxoethyl> oxy) -2-r (phenylmethyl) oxn-A-3-pyridinylbenzamide (E49) (2- { [2- ( { 4 - [(Phenylmethyl) oxy] -3 - [(3-pyridinylamino) carbonyl] phenyl} oxy) ethyl] oxi} ethyl) Bis (1,1-dimethylethyl) midocarbonate (can be prepared as described in description 77; 340 mg, 0.56 mmole) was treated with trifluoroacetic acid / dichloromethane (v / v 40%, 10 ml) . The mixture was stirred at 25 ° C for 1 hr. The solvent was removed under reduced pressure. The residue was purified twice by reverse phase HPLC using a gradient of acetonitrile and 0.1% aqueous ammonia as the eluent. Evaporation of the product containing fractions gave the title compound as a white solid. 86 mg. 1 NMR (400MHz, DMSO-d6): 3.00 (2H, s), 3.68 (2H, s), 3.86 (2H, s), 4.19 (2H, s), 5.18 (2H, s), 7.08-7.20 (3H , m), 7.50 (5H, s), 7.86 (1 H, s), 8.01-8.08 (2H, t), 8.26 (1 H, s), 10.17 (1 H, s) MS (electrospray): m / z [M + H] + = 408 EXAMPLE 50 5-Bromo- / V- (1-methyl-1H-pyrazol-4-yl) -2-f (phenylmethyl) oxnbenzamide (E50) 1-Methyl-1 H -pyrazole-4-amine (61.7 mg, 0.64 mmol) was added in a charge to a stirred suspension of 5-bromo-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as describes in the description 5, 150 mg, 0.49 mmoles), EDC (281 mg, 1.47 mmoles) and HOBT (224 mg, 1.47 mmoles) in N, N-dimethylformamide (3 ml) in air at room temperature. The reaction mixture was stirred at room temperature overnight. 20 ml of water were added and the mixture was extracted with ethyl acetate (20 ml x 2). The combined organic phases were dried over Na 2 SO 4 and concentrated in vacuo to give crude product, which was purified by prep-HPLC (Gilson GX-28; Waters X-Bridge 5 pm 30 * 100 mm; A: 0.1 NH 3 * H 2 O / Water; B: CH3CN) twice to give the title compound as a white solid. 70 mg. 1 H NMR (400 MHz, DMSO-d 6): 3.81 (s, 3 H), 5.25 (s, 2 H), 7.23 (d, 1 H), 7.35-7.42 (m, 4H), 7.50 (d, 2H), 7.64-7.67 (m, 1 H), 7.75 (d, 1 H), 7.97 (s, 1 H), 10.21 (s, 1 H).
MS (electrospray): m / z [M + H] + = 386 EXAMPLE 51 5-Bromo-2-r (phenylmethyl) oxn-A / -1 H -pyrazol-4-ylbenzamide (E51) 1 H-pyrazole-4-amino-ene (55.2 mg, 0.66 mmol) was added in a batch to a stirred solution of 5-bromo-2 - [(phenylmethyl) oxy] benzoic acid (can be prepared as described in US Pat. description 5, method D, 170 mg, 0.55 mmole), EDC (318 mg, 1.66 mmole) and HOBT (254 mg, 1.66 mmole) in?,? - dimethylformamide (4 ml) in air at room temperature. The reaction mixture was stirred at room temperature overnight. Water (30 ml) was added and the mixture was extracted with ethyl acetate (50 ml x 2). The organic layers were combined, dried over MgSO4 and concentrated under vacuum. The residue was washed with ethyl acetate to give the title compound as a brown solid. 180 mg. 1 H NMR (400 MHz, DMSO-d 6): 5.26 (s, 2 H), 7.24 (d, 1 H), 7.35-7.45 (m, 4 H), 7.52 (d, 2 H), 7.65-7.68 (m, 1 H ), 7.77 (d, 1 H), 7.93 (s, 1 H), 10.21 (s, 1 H), 12.66 (s, 1 H).
MS (electrospray): m / z [M + H] + = 372 EXAMPLE 52 A / - (4-Methyl-3-pyridinyl) -2-r (phenylmethyl) oxy-5-4-pyridinium benzamide (E52) A solution of 2 - [(phenylmethyl) oxy] -5- (4-pyridinyl) benzoic acid (can be prepared as described in the description 79; 1 10 mg, 0.33 mmole), EDC (126 mg, 0.66 mmole) and HOBT (101 mg, 0.66 mmol) in dimethylformamide (2 mL) was stirred in air at room temperature for 1 hr. Then, 4-methylpyridin-3-amine (35.6 mg, 0.33 mmol) was added in one charge. The reaction mixture was stirred at 25 ° C overnight. The reaction mixture was diluted with water (25 ml), and then extracted with ethyl acetate (60 ml x 3). The organic phases were combined, washed with brine (50 ml x 3), dried over anhydrous MgSO 4 and concentrated. The residue was purified by CLAR-Prep (instrument: Gilson GX-281, Column: Shimadzu 15 μ? T ?, 250x20mmx2, mobile phase: A = 10mmolNH4HCO3 / water B = CH3CN, Flow rate: 30.0ml / L method: B = 55% ~ 65%, 0.0- 7.2min, B = 65% ~ 95%, 7.2-7.5min, B = 95% ~ 95%, 7.5min ~ 1.5min, RT = 10.0min) to give the compound of the title as a solid rose. 94 mg.
H NMR (400 MHz, DMSO-d6): 9.92 (s, 1 H), 8.77 (s, 1 H), 8.63 (d, 2H, J = 6.0), 8.26 (d, 1 H, J = 4.8), 8.20 (d, 1 H, J = 2.4), 8.01 (dd, 1 H, J = 2.4, 8.8), 7.76 ( d, 2H, J = 6.0), 7.56 (d, 2H, J = 6.8), 7.48 ~ 7.37 (m, 4H), 7.26 (d, 1 H, J = 3.2, 5.39 (s, 2H), 2.02 (s) , 3H).
EM (electro-spray): m / z [M + H] + = 396.1 EXAMPLE 53 / V-r2- (methyloxy) -3-pyridinyl-1-2-r (phenylmethyl) oxn-5- (4-pyridinyl) benzamide (E53) A solution of 2 - [(phenylmethyl) oxy] -5- (4-pyridinyl) benzoic acid (can be prepared as described in the description 79; 1 10 mg, 0.33 mmole), EDC (126 mg, 0.66 mmole) and HOBT (101 mg, 0.66 mmol) in dimethylformamide (2 mL) was stirred in air at room temperature for 1 hr. 2-Methoxy-pyridin-3-amine (40.8 mg, 0.33 mmol) was then added in one charge. The reaction mixture was stirred at 25 ° C overnight. The reaction mixture was diluted with water (25 ml) and then extracted with ethyl acetate (60 ml x 3). The organic phases were combined, washed with brine (50 ml x 3), dried over anhydrous MgSO 4 and concentrated. The residue was purified by CLAR-Prep (instrument: Gilson GX-281.Column: Shimadzu 15 pm, 250 * 20 mm * 2, Mobile phase: A = 10 mmolNH4HC03 / water B = CH3CN, Flow rate: 30.0 ml / L method: B = 80% ~ 90%, 0.0-7.2 min; B = 90% ~ 95%, 7.2-7.5 min; B = 95% ~ 95%, 7.5 min ~ 11.5 min, RT = 1.0 min) to give the title compound as a pink solid. 92 mg. 1 H NMR (400 MHz, DMSO-d 6): 10.40 (s, 1 H), 8.68 (d, 1 H, J = 7.6), 8.64 (d, 2H, J = 5.2), 8.44 (d, 1 H, J = 2.8), 8.04 (dd, H, J = 2.4, J = 8.8), 7.89 (dd, 1 H, J = 1.2, 4.8), 7.73 (d, 2H, J = 6.0), 7.60-7.54 (m, 3H), 7.45-7.38 (m, 3H), 7.04 (dd, 1 H, J = 5.2, 7.6), 5.54 (s, 2H), 3.65 (s, 3H).
MS (electrospray): m / z [M + H] + = 412.20 EXAMPLE 54 A / - (2-Fluoro-3-pyridinyl) -2 - [(phenylmethyl) oxn-5- (4-pyridinyl) benzamide (E54) A solution of 2 - [(phenylmethyl) oxy] -5- (4-pyridinyl) benzoic acid (can be prepared as described in description 79; 0.12 g, 0.34 mmole), EDC (0.16 g, 0.84 mmole) and HOBT (0.13 g, 0.84 mmol) in dimethylformamide (2 mL) was stirred in air at room temperature for 1 hr. 2-Fluoropyridin-3-amine (0.04 g, 0.37 mmol) was then added in a load. The reaction mixture was stirred at 25 ° C overnight. Another batch of HOBT (0.13 g, 0.84 mmol), EDC (0.61 g, 0.842 mmol) and 2-fluoropyridin-3-amine (0.04 g, 0.37 mmol) was added to the mixture and heating was continued at 40 ° C. C for 38 hours. The reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (60 ml x 3). The organic phases were combined, washed with brine (50 ml x 3), dried over anhydrous MgSO 4 and concentrated. The residue was purified by chromatography (silica gel, 40 g, eluent: dichloromethane / methanol = 50: 1, 1 L). The solid was washed with methanol (3 ml x 2) and dried under vacuum to give the title compound as a gray solid. 31 mg.
H NMR (400 Hz, DMSO-d6): 10.31 (s, 1 H), 8.64-8.61 (m, 3H), 8.26 (d, 1 H, J = 2.0), 8.04 (dd, 1 H, J = 2.4 , 9.2), 7.97 (d, 1 H, J = 4.8), 7.74 (dd, 2H, J = 1.6, 4.8), 7.56 (d, 2H, J = 7.2), 7.50 (d, 1 H, J = 8.8 ), 7.43-7.36 (m, 4H), 5.42 (s, 2H).
MS (electrospray): m / z [M + H] + = 400.0 EXAMPLE 55 / V-r2- (Hydroxymethyl) -3-pyridinium-2 - [(phenylmethyl) oxn-5- (4-pyridm (E55) (3-Aminopyridin-2-yl) methanol net (can be prepared as described in the description 80; 68 mg, 0.55 mmole) was added in a charge to a stirred suspension of 2 - [(phenylmethyl) oxy] ] -5- (4-pyridinyl) benzoic acid (can be prepared as described in the description 79; 120 mg, 0.393 mmol), EDC (151 mg, 0.786 mmol), HOBT (120 mg, 0.79 mmol) and triethylamine (0.11) mi, 0.79 mmole) in?,? - dimethylformamide (1.5 ml) in air at 15 ° C. The reaction mixture was stirred at 15 ° C overnight. Water (30 ml) was added and the reaction mixture was extracted with ethyl acetate (30 ml x 3). The organic phases were dried with Na 2 SO 4 and concentrated. The residue was purified by CLAR-prep (instrument: Gilson-281, Column: WATERS XBRIDGE 30-100MM SUM, Mobile phase: A: 0.04% NH3H2O B: CH3CN, Flow rate: 30.0 ml / L, Gradient: 0-10 min, B = 30-38% RT = P1: 7.0 min; P2: 9.5 min) to give the title compound as a white solid. 20 mg. 1 H NMR (400MHz, DMSO-d 6); 10.82 (s, 1 H), 8.57-8.63 (m, 3H), 8. 35-8.36 (m, H), 8.27-8.29 (m, 1 H), 7.95-7.97 (m, 1 H), 7.70-7.71 (m, 2H), 7.53-7.55 (m, 2H), 7.32-7.41 (m, 5H), 5.54 (s, 2H), 4.65 (s, 2H).
MS (electrospray): m / z [M + H] + = 412 EXAMPLE 56 / V-f4- (Hydroxymethyl) -3-pyridinin-2-f (phenylmethyl) oxn-5- (4-pyrid) ÍE56] (3-Aminopyridin-4-yl) methanol net (can be prepared as described in description 81; 103 mg, 0.83 mmol) was added in a charge to a stirred suspension of 2 - [(phenylmethyl) oxy] -5 - (4-pyridinyl) benzoic acid (can be prepared as described in description 79; 180 mg, 0.59 mmole), EDC (226 mg, 1.18 mmole), HOBT (181 mg, 1179 mmole) and triethylamine (0.16 ml, 1.18 mmoles) in N, N-dimethylformamide (1.5 ml) in air at 15 ° C. The reaction mixture was stirred at 15 ° C overnight. 100 ml of water were added. The solid was filtered and then purified by HPLC-prep (instrument: Gilson-281. Column: Shimadzu 5 pm: 250 * 20 mm * 2, Mobile phase: A: 10 m ol / LNH4HC03, B: CH3CN, Flow rate : 30.0 ml / L, Gradient: B: 43-55% at 0-7.2 RT = 7.5 min, 0.5) to give the compound of the title as a white solid. 57 mg.
H NMR (400MHz, DMSO-d6): 10.29 (s, 1 H), 8.90-8.92 (m, 2H), 8.62-8.63 (m, 2H), 8.39-8.40 (m, 1 H), 8.24-8.25 ( m, 1 H), 7.96-7.99 (m, 1 H), 7.73-7.75 (m, 2H), 7.53-7.55 (m, 2H), 7.47-7.48 (m, 1 H), 7.33-7.42 (m, 4H), 5.56 (t, 1 H, J = 5.2), 5.46 (s, 2H), 4.53 (d, 2H, J = 5.2).
MS (electrospray): m / z [M + H] + = 412.0 EXAMPLE 57 5-Bromo-2- (f (3-fluoropheninmethyl) -oxiVA / -3-pyridinylbenzamide (E57) Net pyridine-3-amine (16 mg, 1.23 mmol) was added in a charge to a stirred suspension of 5-bromo-2- acid. { [(3-fluorophenyl) methyl] oxy} benzoic acid (can be prepared as described in the description 83; 200 mg, 0.62 mmol), EDC (354 mg, 1.85 mmol), HOBT (283 mg, 1.85 mmol) and triethylamine (0.26 ml, 1.85 mmol) in N, N dimethylformamide (6 ml) in air at room temperature. The reaction mixture was stirred at 25 ° C overnight. Water (25 ml) was added and the mixture was extracted with ethyl acetate (20 ml x 3). The organic phase was washed with saturated brine (10 mL), water (25 mL), dried over sodium sulfate and evaporated under vacuum. The residue was purified with CCD-Prep (eluted product: dichloromethane: methanol = 25: 1) to obtain crude product which was washed with methanol (4 mL) to give the title compound as a white solid. 33 mg. 1 H NMR (400MHz, DMSO-d 6): 9.85 (brs, 1 H), 8.45 (d, 1 H, J = 2A), 8.35 (brs, 1 H), 8.15-8.18 (m, 2H), 7.65 (dd) , 1 H, J = 2.4, J = 8.8), 7.49-7.54 (m, 1 H), 7.34-7.35 (m, 1 H), 7.20-7.28 (m, 3H), 7.04 (d, 1 H, J = 8.8), 5.24 (s, 2H).
EM (electroaspersion): m / z [M + H] + = 401.0, 403.0 EXAMPLE 58 5-Bromo-2- (r (2-fluorophenyl) methyloxy) -A-3-pyridinylbenzamide (E58) Net pyridine-3-amine (82 mg, 0.87 mmol) was added in a charge to a stirred solution of 5-bromo-2- acid. { [(2-fluorophenyl) methyl] oxy} benzoic acid (can be prepared as described in the description 85; 200 mg, 0.58 mmol), EDC (223 mg, 1.16 mmol) and HOBT (178 mg, 1.16 mmol) in dimethylformamide (3 mL) in air at room temperature. The reaction mixture was stirred at 25 ° C overnight. Water (25 ml) was added to the reaction mixture. The precipitate was filtered, washed with water (15 ml) and dried under vacuum to obtain crude product, which was purified with CCD-Prep (eluted product: dichloromethane: methanol 25: 1) to give the title compound as a solid. White. 67 mg. 1 H NMR (400 MHz, CDCl 3): 9.85 (s, 1 H), 8.42 (t, 1 H, J = 2.4), 8. 31 (s, 1 H), 8.23 (d, 1 H, J = 8.4), 8.06 (s, 1 H), 7.64 (m, 1 H), 7.51 (m, 2H), 7.26 (m, 3H), 7.08 (dd, 1 H, J = 2, J = 8.4), 5.32 (s, 2H).
MS (electrospray): m / z [M + H] + 400.9 EXAMPLE 59 5-Bromo-2- (r (4-fluorophenyl) methyloxy) -A / -3-pyridinylbenzamide (E59) Net pyridine-3-amine (79 mg, 0.84 mmol) was added in a charge to a stirred solution of 5-bromo-2- acid. { [(4-fluorophenyl) methyl] oxy} benzoic acid (can be prepared as described in the description 87; 200 mg, 0.56 mmol), EDC (213 mg, 1.1 1 mmol) and HOBT (170 mg, 1.1 mmol) in DMF (3 ml) at room temperature. The reaction mixture was stirred at 25 ° C overnight. Water (25 ml) was added and the solid filtered, washed with water (15 ml) and dried under vacuum. The residue was further purified with CCD-Prep (eluted product: dichloromethane: methanol = 25: 1) to give the title compound as a white solid. 76 mg.
HRN (400 MHz, CDCl 3): 9.89 (s, 1 H), 8.45 (d, 1 H, J = 2.4), 8.33 (d, 1 H, J = 2.0), 8.15 (s, 1 H), 8.09 ( d, 1 H, J = 8.0), 7.64 (dd, 1 H, J = 2.4, 8.4), 7.54 (dd, 2H, J = 5.2, 8.4), 7.27-7.20 (m, 3H), 7.05 (d, H, J = 8.8), 5.22 (s, 2H).
MS (electrospray): m / z [M + H] + = 400.9 Method B Diisopropylethylamine (1.34 ml, 7.69 mmol), 3-aminopyridine (0.43 g, 4.61 mmol) and HATU (2.19 g, 5.77 mmol) were added to a solution of 5-bromo-2- acid. { [(4-fluorophenyl) methyl] oxy} benzoic acid (can be prepared as described in description 87; 1.25 g, 3.84 mmol) in N, N-dimethylformamide (10 ml). The mixture was stirred for 2 hours. The solid was then filtered and washed with ethyl acetate to give the title compound as a white solid. 650 mg.
MS (electrospray): m / z [M + H] + = 402/404 1 H NMR (DMSO-c / 6): 5.22 (2 H, s), 7. 0- 7.31 (3 H, m), 7.37 (1 H, dd, J = 8.33, 4.82 Hz), 7.55 (2 H, dd, J = 8.55, 5.70 Hz), 7.69 (1 H, dd, J = 8.77, 2.63 Hz), 7.77 (1 H, d, J = 2.63 Hz), 8.08 (1 H, dt, J = 8.33, 1.97 Hz), 8.29 (1 H, dd, J = 4.71, 1.43 Hz), 8.70 (1H, d, J = 2.19 Hz), 10.40 (1 H, s) EXAMPLE 60 5-Bromo-2-. { f (3,4-difluorophenyl) methyloxy > -jV-3-pyridinylbenzamide (E60) Method A Net pyridine-3-amine (105 mg, 1.11 mmol) was added in a charge to a stirred solution of 5-bromo-2- acid. { [(3,4-difluorophenyl) methyl] oxy} benzoic acid (can be prepared as described in the description 89; 300 mg, 0.74 mmol), EDC (284 mg, 1.48 mmol), HOBT (227 mg, 1.48 mmol) in dimethylformamide (3 mL) in air at room temperature. The reaction mixture was stirred at 25 ° C overnight. Water (50 ml) was added to the reaction mixture. The precipitate was filtered, washed with water (15 ml) and dried under vacuum. The residue was washed with methanol / chloromethane (50: 1, 8 ml) and dried under vacuum to give the title compound as a white solid. 248 mg.
H NMR (400 MHz, CDCl 3): 9.75 (s, 1 H), 8.44 (d, 1 H, J = 2.4), 8.35 < s, 1 H), 8.25 (s, 1 H), 8.13 (d, 1 H, J = 8.0), 7.63 (d, 1 H, J = 2.4, 8.4), 7.39-7.26 (m, 4H), 7.01 (d, 1 H, J = 8.8), 5.21 (s, 2H).
LCMS: MH + = 419 Method B 3-Pyridinamine (0.28 g, 2.94 mmol), HATU (2.22 g, 5.83 mmol) and diisopropylethylamine (1.53 ml, 8.74 mmol) were added to a solution of 5-bromo-2- acid. { [(3,4-difluorophenyl) methyl] oxy} benzoic acid (can be prepared as described in the description 89; 1 g, 2.91 mmol) in N, N-dimethylformamide (25 ml). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (200 ml), stirred and allowed to stand for 5 min. The solid precipitate was filtered, washed with water (25 ml) and ethyl acetate (50 ml) and dried under vacuum to give a white solid. 380 mg.
MS (electrospray): m / z [M + H] + = 420 EXAMPLE 61 A / - (3-ethyl-4-isoxazolyl) -2-r (phenylmethyl) oxn-5- (4-pyridinyl) benzamide (E61) a mixture of 2 - [(phenylmethyl) oxy] -5- (4-pyridinyl) benzoic acid (can be prepared as described in description 79; 0.12 g, 0.36 mmole), EDC (0.14 g, 0.72 mmole) and HOBT (0.1 1 g, 0.72 mmol) in N, N- dimethylformamide (2 ml) was stirred in air at room temperature for 1 hr, then 3-methyl-4-isoxazolamine (can be prepared as described in description 91; 100 mg, 1.02 mmol) was added in one charge. The reaction mixture was stirred at 25 ° C overnight. The reaction mixture was diluted with water (25 ml). The solid was filtered, washed with water (30 ml) and methanol (5 ml x 2) and dried under vacuum to give the title compound as a gray solid. 72 mg. 1 H NMR (400 MHz, DMSO-d 6): 9.97 (s, 1 H), 9.19 (s, 1 H), 8.63 (d, 2 H, J = 6.0), 8.18 (d, 1 H, J = 2.4), 8.04 (dd, H, J = 2.4, J = 8.8), 7.75 (d, 2H, J = 6.0), 7.56 (d, 2H, J = 6.8), 7.49-7.38 (m, 4H), 5.34 (s, 2H), 1.95 (s, 3H).
MS (electrospray): m / z [M + H] + = 386.00 EXAMPLE 62 A / - (5-Methyl-4-isoxazolih-2-f (phenylmethyl) oxy1-5- (4-pyridinyl) benzamide (E62) A mixture of 2- [. { phenylmethyl) oxy] -5- (4-pyridinyl) benzoic acid (can be prepared as described in description 79; 100 mg, 0.30 mmol), EDC (15 mg, 0.60 mmol), and HOBT (92 mg, 0.60 mmol) ) in dimethylformamide (2 ml) was stirred in air at room temperature for 1 hr, then 5-methyl-4-isoxazolamine (can be prepared as described in description 93; 100 mg, 1.02 mmol) was added in one charge. The reaction mixture was stirred at 25 ° C overnight. The solution was heated at 35 ° C for 7 hours, then diluted with water (30 ml) and extracted with ethyl acetate (80 ml x 3). The organic phase was washed with brine (60 ml x 2), dried over anhydrous MgSO 4 and concentrated. The residue was purified by chromatography (silica gel, 20 g, eluent. Dichloromethane / methanol = 60: 1, 600 ml). The crude product was washed with methanol (2 ml x 2), filtered and dried under vacuum to give the title compound. 23 mg.
H NMR (400 MHz, DMSO-d6): 9.95 (s, H), 8.82 (s, H), 8.62 (d, 2H, J = 6.4), 8.10 (d, 1 H, J = 2.4), 8.00 (dd, 1 H, J = 2.0, J = 8.4), 7.74 (dd, 2H, J = 1 .2, 4.8), 7.54 (d, 2H, J = 7.2), 7.44-7.34 (m, 4H), 5.33 (s, 2H), 2.22 (s, 3H).
EM (electrospray): m / z [M + H] + = 386.1 EXAMPLE 63 A / -4-lsoxazolyl-2-r (phenylmethyl) oxn-5- (4-pyridinyl) benzamide (E63) mixture of 2 - [(phenylmethyl) oxy] -5- (4-pyridinyl) benzoic acid can prepare as described in description 79; 100 mg, 0.30 mmol), EDC (172 mg, 0.90 mmol) and HOBT (137 mg, 0.90 mmol) in dimethylformamide (3 mL) was stirred in air at room temperature for 1 hr, then 4-isoxazolamine (can be prepared as described in the description 95, 100 mg, 1189 mmol) was added in one charge. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (30 ml). The solid was filtered and dried under vacuum to obtain crude product, which was purified with CLAR-Prep (Waters, X-Bridge, 5 μm; 30 × 100 mm; A = 0.05% NH3.H 2 O / water, B: MeCN; v = 30 ml / min, 0-7 min, 42% -54%, 7-12min, 95%, t = 8.0min.) to give the title compound as a white solid. 34 mg. 1 H NMR (400 MHz, DMSO-d 6): 10.60 (s, 1 H), 9.27 (s, 1 H), 8.65 (s, 1 H), 8.62 (d, 2 H, J = 5.6), 8.08 (d, 1 H, J = 2.0), 7.98 (dd, 1 H, J = 2.0, 8.4), 7.74 (d, 2H, J = 5.6), 7.52 (d, 2H, J = 7.6), 7.42-7.33 (m, 4H), 5.36 (s, 2H).
EM (electroaspersion); m / z [M + H] + = 372.1 EXAMPLE 64 2 - [(Phenylmethyl) oxn-N-1H-pyrazol-4-yl-5- (4-pyridinyl) benzamide (E64) 1 H-pyrazole-4-amine net (49.0 mg, 0.59 mmol) was added in a charge to a stirred solution of 2 - [(phenylmethyl) oxy] -5- (4-pyndinyl) benzoic acid (can be added prepare as described in description 79; 150 mg, 0.49 mmol), EDC (283 mg, 1.47 mmol) and HOBT (226 mg, 1.47 mmol) in dimethylformamide (4 mL) in air at room temperature. The reaction mixture was stirred at room temperature overnight. 30 ml of water were added and the mixture was extracted with ethyl acetate (70 ml x 2). The organic layers were combined, dried over MgSO4 and concentrated in vacuo. The residue was further purified by HPLC-prep (Gilson GX-28; Shimadzu 15 pM 250 * 20mm; A: 10m or NH4HC03 / Water; B: CH3CN) to give the title compound as a white solid. 50 mg. 1 H NMR (400 Hz, DMSO-d 6): 5.34 (s, 2 H), 7.34-7.44 (m, 4 H), 7.55 (d, 2 H), 7.74 (d, 4 H), 7.95-7.98 (m, 1 H) , 8.09 (d, 1 H), 8.62 (d, 2H), 10.25 (s, 1 H), 12.65 (s, 1 H).
MS (electrospray): m / z [M + H] + = 371 EXAMPLE 65 ? 1 -Methyl-1 H -pyrazol-4-yl) -2-r (phenylmethyl) oxyl-5- (4-pyridinyl) benzamide (E65) 1-Methyl-1 H-pyrazole-4-amine (38.2 mg, 0.39 mmol) was added in a charge to a stirred solution of 2- [. { phenylmethyl) oxy] -5- (4-pyridinyl) benzoic acid (can be prepared as described in description 79; 100 mg, 0.33 mmole), EDC (188 mg, 0.98 mmole) and HOBT (150 mg, 0.983 mmole) in dimethylformamide (3 ml) in air at room temperature. The reaction mixture was stirred at room temperature overnight. Water (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml x 2). The organic phase was dried over Na2SO4 and concentrated in vacuo to give crude product, which was purified by HPLC-prep (Gilson GX-28; Waters X-Bridge 5 pm 30 * 100 mm; A: 0.1 M NH3.H2O / water; B: CH3CN) twice to give the title compound as a white solid. 58 mg. 1 H NMR (400 MHz, DMSO-c / 6): 3.82 (s, 3 H), 5.33 (s, 2 H), 7.35-7.43 (m, 5 H), 7.54 (d, 2 H), 7.73 (d, 2 H), 7.95-7.97 (m, 1 H), 8.00 (s, 1 H), 8.06 (d, 1 H), 8.62 (d, 2H), 10.25 (s, 1 H).
LCMS: MH + = 385 EXAMPLE 66 5-Formyl-2-f (phenylmethyl) oxy1-A / -3-pyridinylbenzamide (E66) Diisopropylethylamine (0.95 ml, 5.46 mmol), 3-aminopyridine (514 mg, 5.46 mmol) and HATU (1.56 g, 4.1 mmol) were added to a solution of 5-formyl-2 - [(phenylmethyl) oxy] benzoic acid (mp). can be prepared as described in the description 97; 770 mg, 2.73 mmol) in dimethylformamide (10 ml). The solution was stirred for 72 hours. Ethyl acetate (40 ml) and H20 (40 ml) were added and the organic layer was washed with H20 (3 x 20 ml), dried and the solvent removed under vacuum to give a solid. The solid was purified by column chromatography (ethyl acetate) to give the title compound as a white solid (300 mg).
MS (electrospray): m / z [M + H] + = 333 H NMR (DMSO-c / 6): 5.37 (2H, s), 7.27-7.44 (4H, m), 7.47-7.61 (3H, m), 8.01-8.14 (2H, m), 8.18 (1 H, d, J = 1.97 Hz), 8.30 (1 H, dd, J = 4.71, 1.43 Hz), 8.72 (1 H, d, J = 2.41 Hz), 9.97 (1 H, s), 10.47 (1 H, s) EXAMPLE 67 5 (E / Z) - (Hydroxyimino) metn-2 - [(phenylmethyl) oxy-N-3-pyridinylbenzamide ÍE67J Pyridine (0.24 ml, 3.01 mmol) and hydroxylamine hydrochloride (42 mg, 0.60 mmol) were added to a solution of 5-formyl-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in Example 66, 100 mg, 0.301 mmol) in methanol (5 ml). A solid left the solution in 5 minutes and the mixture was stirred for an additional 10 minutes. The solid was filtered and washed with methanol (10 mL) and water (100 mL) to give the title compound as an off-white solid. 80 mg.
MS (electrospray): m / z [M + H] + = 348 1 H NMR (DMSO-c / 6): 5.20-5.35 (2 H, m), 7.25-7.44 (5 H, m), 7.48-7.61 (2 H, m), 7.74 (1 H, dd, J = 8.66 , 2.08 Hz), 7.89 (1 H, d, J = 1.97 Hz), 8.03-8.20 (2 H, m), 8.28 (1 H, dd, J = 4.71, 1.42 Hz), 8.69 (1 H, d, J = 2.41 Hz), 10.41 (1 H, s), 1 1.15 (1 H, s) EXAMPLE 68 (2Z) -3- (4-f (phenylmethyl) oxn-3-r (3-pyridinylamino) carbonylphenyl) -2-ethyl propenoate (E68) KHMDS 0.5N (1.81 mL, 0.90 mmol) was added to a solution of triethyl phosphonoacetate (0.20 g, 0.90 mmol) in tetrahydrofuran (5 mL) at -78 ° C. The solution was stirred at -78 ° C for 15 minutes, then a suspension of 5-formyl-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in Example 66; 200 mg, 0.60 mmoles) in tetrahydrofuran (10 ml) was added dropwise over 3 minutes. The mixture was stirred at -78 ° C for 15 minutes. It was then allowed to warm to room temperature and stirred for an additional hour. The reaction was quenched with saturated NH 4 Cl (10 mL) and extracted with ethyl acetate (2 mL). The combined organic layers were dried (MgSO4) and the solvent was removed under vacuum to give a brown solid. Trituration with 2: 1 ethyl acetate / hexane gave the title compound as a brown solid. 160 mg.
MS (electrospray): m / z [M + H] + = 403 1 H NMR (DMSO-c / 6): 1.26 (3 H, t, J = 7.13 Hz), 4.18 (2 H, q, J = 7.16 Hz), 5.29 (2 H, s), 6.61 (1 H, d, J = 16.00 Hz), 7.27-7.42 (5 H, m), 7.51 (2 H, d, J = 6.58 Hz), 7.67 (1 H, d, J = 16.00 Hz), 7.90 (1 H, dd, J = 8.66, 2.30 Hz), 7.98 (1 H, d, J = 2.19 Hz), 8.12 (1 H, dt, J = 8.28, 1.89 Hz), 8.29 (1 H, dd, J = 4.71, 1.43 Hz), 8.74 (1 H, d, J = 2.19 Hz), 10.45 (1 H, s) EXAMPLE 69 5- (4-Morpholinylmethyl) -2-f (phenylmethyl) oxy 1-N-3-pyridinylbenzamide (E69) Morpholine (26 uL, 0.30 mmol) and acetic acid (17 ul, 0.30 mmol) were added to a solution of 5-formyl-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in US Pat. Example 66, 100 mg, 0.301 mmol) in DCE (5 ml). The solution was stirred for 4 hours at 50 ° C, then sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added. The reaction was stirred overnight. Saturated NaHCO3 solution (50 mL) was added and the mixture was stirred for 5 minutes. Then, the organic layer was diluted with dichloromethane (5 ml), before being separated and dried (MgSO 4). The solvent was removed under vacuum and the residue was purified by MDAP to give the title compound. 40 mg.
MS (electrospray): m / z [M + H] = 418 1 H NMR (DMSO-d 6): 2.26-2.42 (4 H, m), 3.34 (2 H, br. S.). 3.57 (4 H, t, J = 4.38 Hz), 5.24 (2 H, s), 7.20-7.49 (6 H, m), 7.51-7.57 (2 H, m), 7.63 (1 H, d, J = 1.97 Hz), 8.08 (1 H, dd, J = 8.33, 1.53 Hz), 8.27 (1 H, dd, J = 4.60, 1.53 Hz), 8.65 (1 H, d, J = 2.41 Hz), 10.33 (1 H, s) EXAMPLE 70 2 (Phenylmethyl) oxy1- / V-3-pyridinyl-5- (1-pyrrolidinylmethylbenzamide (E70) Pyrrolidine (25 uL, 0.30 mmol) and acetic acid (17 uL, 0.30 mmol) were added to a solution of 5-formyl-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in Example 66, 100 mg, 0.30 mmol) in DCE (5 ml). The solution was stirred for 4 hours at 50 ° C then sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added. The reaction was stirred overnight then quenched with NaHCO3 solution (7 mL) and extracted with dichloromethane (5 mL). The organic layer was dried (MgSO4) and the solvent was removed under vacuum to give a yellow solid. The residue was purified by MDAP to give the title compound as an opaque solid. 34 mg.
EM (electrospray): m / z [+ H] + = 388 H NMR (DMSO-c / 6): 1.71 (4 H, br. S.), 3.44 (6 H, br. S.), 5.24 (2 H, s), 7.18-7.42 (4 H, m), 7.46 (1 H, dd, J = 8.44, 2.08 Hz), 7.54 (2 H, d, J = 6.36 Hz), 7.64 (1 H, d, J = 1.97 Hz), 8.03-8.12 (1 H, m) , 8.17- 8.30 (2 H, m), 8.65 (1 H, d, J = 2.19 Hz), 10.33 (1 H, s) EXAMPLE 71 5 - [(Dimethylamino) metin-2-r (phenylmethyl) oxy-1-V-3-pyridinylbenzamide (E71) Dimethylamine (60 uL, 0.33 mmol) and acetic acid (19 uL, 0.33 mmol) were added to a solution of 5-formyl-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in Example 66, 100 mg, 0.33 mmole) in DCE (5 ml). The solution was stirred for 3 hours at 50 ° C then sodium triacetoxyborohydride (105 mg, 0.50 mmol) was added. The mixture was stirred overnight. Then, saturated NaHCO3 solution (5 mL) was added and the mixture was stirred for 5 minutes. The organic layer was diluted with dichloromethane (5 mL), separated and dried (MgSO4). The solvent was removed under vacuum and the residue was purified by MDAP to give the title compound as an opaque solid. 17 mg.
MS (electrospray): m / z [M + H] + = 362 1 H NMR (D SO-d 6): 2.15 (6 H, s), 3.50 (2 H, br. S.), 5.24 (2 H, s), 7.16-7.47 (6 H, m), 7.50-7.66 ( 3 H, m), 8.02- 8.14 (1 H, m), 8.27 (1 H, dd, J = 4.82, 1.32 Hz), 8.65 (1 H, d, J = 2.19 Hz), 10.33 (1 H, s ) EXAMPLE 72 5-Acetyl-2-r (phenylmethyl) oxy1-rV-3-pyridinylbenzamide (E72) Diisopropylethylamine (0.97 ml, 5.55 mmol), 3-aminopyridine (418 mg, 4.44 mmol) and HATU (1.27 g, 3.33 mmol) were added to a solution of 5-acetyl-2 - [(phenylmethyl) oxy] benzoic acid (commercially available from Acros, 600 mg, 2.22 mmol) in dimethylformamide (10 ml). The solution was stirred for 2 hours. Ethyl acetate (40 ml) and H20 (40 ml) were added and the organic layer was washed with H20 (3 x 20 ml), dried and the solvent removed under vacuum to give a solid. Trituration with hexane / ethyl acetate 3: 1 gave the title compound as a yellow solid. 541 mg.
MS (electrospray): m / z [M + H] + = 347 1 H NMR (SO-C / 6 D): 2.58 (3 H, s), 5.35 (2 H, s), 7.28-7.46 (5 H, m), 7.53 (2 H, d, J = 6.36 Hz), 8.06-8.18 (2 H, m), 8.22 (1 H, d, J = 2.41 Hz), 8.29 (1 H, dd, J = 4.60, 1.32 Hz), 8.73 (1 H, d, J = 2.41 Hz) , 10.46 (1H, s) EXAMPLE 73 5- (1-Methyl-1H-pyrazol-4-yl) -2-r (phenylmethyl) oxy1-A / -4-pyridazinylbenzamide (E73) 1-Methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -H-pyrazole (56.9 mg, 0.273 mmol), 1 M Na2C03 (0.52 ml, 0.52 mmol) ) and tetrakis (triphenylphosphino) palladium (0) (18 mg, 6 mol%) were added to a solution of 5-bromo-2 - [(phenylmethyl) oxy] -N-4-pyridazinylbenzamide (can be prepared as described in Example 6; 100 mg, 0.26 mmol) in 1,2-dimethoxyethane (3 mL). The solution was heated to 140 ° C in the microwave for 35 minutes. The solvent was removed under vacuum to give a residue. Trituration with 1: 1 dimethyl sulfoxide / methanol (0.6 ml) gave the product as a solid which was washed with methanol (2 ml) and ethyl acetate (5 ml) to give the title compound as a gray solid. 45 mg.
MS (electrospray): m / z [M + H] + = 386 HRN (DMSO-d6): 3.85 (3 H, s), 5.24 (2 H, s), 7.21-7.41 (4 H, m), 7.50 (2 H, d, J = 6.58 Hz), 7.71 (1 H , dd, J = 8.55, 1.97 Hz), 7.79 (1 H, d, J = 1.97 Hz), 7.86 (1 H, s), 8.02 (1 H, dd, J = 5.81, 2.74 Hz), 8.14 (1 H, s), 9.02 (1 H, d, J = 5.70 Hz), 9.22 (1 H, br. S.), 10.84 (1 H, br. S.) EXAMPLE 74 2-r (Phenylmethyl) oxn- / V-4-pyridazinyl-5- (4-pyridinyl) benzamide (E74) 4-boronic acid pyridine (35.2 mg, 0.29 mmol), 1 M Na2C03 (0.52 ml, 0.52 mmol) and tetrakis (triphenylphosphino) palladium (0) (18 mg, 6 mol%) were added to a solution of 5-bromo- 2 - [(phenylmethyl) oxy) -N-4- pyridazinylbenzamide (can be prepared as described in Example 6; 100 mg, 0.26 mmol) in 1,2-dimethoxyethane (3 mL). The solution was heated to 140 ° C in the microwave for 25 minutes. The solvent was removed under vacuum and the residue was purified by MDAP to give the title compound as an off-white solid. 22 mg.
MS (electrospray): m / z [M + H] + = 383 1 H NMR (DMSO-d 6): 5.32 (2 H, s), 7.22-7.58 (6 H, m), 7.70-7.82 (2 H, m), 7.97-8.16 (3 H, m), 8.56-8.69 ( 2 H, m), 9.02-9.14 (1 H, m), 9.29 (1 H, d, J = 1.97 Hz), 10.93 (1 H, s) EXAMPLE 75 5- (1-Hydroxyethyl) -2-r (phenylmethyl) oxy-N-3-pyridinylbenzamide (E75) Sodium borohydride (32.8 mg, 0.87 mmol) and boric acid (53.6 mg, 0.87 mmol) were added to a suspension of 5-acetyl-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in Example 72; 100 mg, 0.29 mmol) in ethanol (5 ml). The mixture was stirred for one hour and then quenched using saturated NaHCO 3 solution (5 mL). The mixture was extracted with dichloromethane (3 x 5 mL). The organic layers were dried (MgSO4) and the solvent was removed under vacuum. The residue was purified by MDAP to give the title compound as a golden colored solid. 62 mg.
MS (electrospray): m / z [M + H] + = 349 1 H NMR (DMSO-d 6): 1.33 (3 H, d, J = 6.58 Hz), 4.74 (1 H, dd, j = 6.14, 4.60 Hz), 5.20 (1 H, d, J = 4.38 Hz), 5.24 (2 H, s), 7.25 (1 H, d, J = 8.55 Hz), 7.30-7.42 (4 H, m), 7.43-7.59 (3 H, m), 7.68 (1 H, d, J = 1.97 Hz), 8.02-8.15 (1 H, m), 8.27 (1 H, dd, J = 4.82, 1.32 Hz), 8.66 (1 H, d, J = 2.41 Hz), 10.34 (1 H, s) EXAMPLE 76 5- (1-Hydroxy-1-methylethyl) -2-f (phenylmethyl) oxy-N-3-pyridine-benzamide (E76) 3M Ethylmagnesium bromide (0.10 ml, 0.29 mmol) was added to a solution of 5-acetyl-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in Example 72; 100 mg, 0.29 mmol) in tetrahydrofuran (3 mL) at 0 ° C. The solution was stirred for 45 minutes. Another 3 equivalents of 3M methylmagnesium bromide (300 ul) were added at 0 ° C and the solution was stirred for 18 hours. Then, 1N H 2 SO 4 (5 mL) was added, the mixture was stirred for 3 minutes, then ethyl acetate (10 mL) was added.
The acid layer was basified to pH 9 using saturated NaHCO3 solution. The organic layer was washed with saturated NaHCO 3 solution (5 mL), dried (MgSO 4) and the solvent removed under vacuum. The residue was purified by MDAP to give the title compound as a white solid. 61 mg.
MS (electrospray): m / z [M + H] + = 363 1 H NMR (DMSO-c / 6): 1.43 (6 H, s), 5.09 (1 H, s), 5.24 (2 H, s), 7.22 (1 H, d, J = 8.77 Hz), 7.28-7.43 (4 H, m), 7.46-7.63 (3 H, m), 7.79 (1 H, d, J = 2.19 Hz), 8.03-8.14 (1 H, m), 8.27 (1 H, dd, 4.71, 1.42 Hz), 8.66 (1 H, d, J = 2.19 Hz), 10.34 (1 H, s) EXAMPLE 77 5-Bromo-2- f (4-fluorophenyl) methynoxy) -N-4-pyridazinylbenzamide (E77) Diisopropylethylamine (1.61 ml, 9.23 mmol), 4-pyridazinamine (0.53 g, 5.54 mmol) and HATU (2.63 g, 6.92 mmol) were added to a solution of 5-bromo-2- acid. { [(4-fluorophenyl) methyl] oxy} benzoic acid (can be prepared as described in the description 87; 1.5 g, 4.61 mmol) in N, N-dimethylformamide (10 ml). The mixture was stirred for 2 hours and the solid was filtered and washed with ethyl acetate to give the title compound as a white solid. 658 mg.
E (electroaspersion): m / z [M + H] + = 402/404 H NMR (DMSO-d6): 5.21 (2 H, s), 7.10-7.24 (2 H, m), 7.27 (1 H, d, J = 8.99 Hz), 7.53 (2 H, dd, J = 8.66, 5.59 Hz), 7.67- 7.82 (2 H, m), 8.00 (1 H, dd, J = 5.92, 2.85 Hz), 9.07 (1 H, d, J = 5.92 Hz), 9.25 (1 H, d, J = 1.75 Hz), 10.85 (1 H, s) EXAMPLE 78 5-Bromo-2- (f (3,4-difluorophenyl) methyloxy) - V-4-pyridazinylbenzamide (E78) 4-Pyridazinamine (0.42 g, 4.37 mmol), HATU (2.22 g, 5.83 mmol) and diisopropylethylamine (1.53 ml, 8.74 mmol) were added to a solution of 5-bromo-2- acid. { [(3,4-difluorophenyl) methyl] oxy} benzoic acid (can be prepared by the description 89; 1 g, 2.91 mmol) in N, N-dimethylformamide (25 ml). The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (200 ml), stirred and allowed to stand for 5 min. The precipitate was filtered, washed with water (25 ml) and ethyl acetate (50 ml) and dried under vacuum to give the title compound as a white solid. No further purification was carried out. 900 mg.
E (electroaspersion): m / z [M + H] + = 421 EXAMPLE 79 2- (f (3,4-Difluorophenyl) methyloxy> -5-formyl-N-4-pyridazinylbenzamide (E79) EDC (0.79 g, 4.11 mmol), HOBT (0.84 g, 5.48 mmol), N-ethylmoricololine (0.87 mL, 6.84 mmol) and 4-pyridazinamine (0.49 g, 5.13 mmol) were added to a solution of 2- acid. { [(3,4-difluorophenyl) methyl] oxi} -5-formylbenzoic acid (can be prepared by the description 101; 1 g, 3.42 mmol) in?,? - dimethylformamide (DMF; 25 ml) and the mixture was stirred at room temperature. The DMF was evaporated under reduced pressure and the residue was diluted with ethyl acetate (100 ml) and the organic layer was washed with saturated sodium bicarbonate (2 x 50 ml) and water (2 x 50 ml). The organic layer was dried (MgSO 4), filtered and evaporated under reduced pressure to give the title compound as a dark yellow solid. 0.98 g.
MS (electrospray): m / z [M + H] + = 370 EXAMPLE 80 2- (G? 3,4 - ????? G? (????)? T? 6 ?????? > -5 - ?? G ???? -? / - 3- p <-1 ???? 6ß ?? 3 ???? 3 (E80) EDC (0.79 g, 4.1 1 mmol), HOBT (0.84 g, 5.48 mmol), N-ethylmorpholine (0.87 mL, 6.84 mmol) and 3-pyridinamine (0.48 g, 5.13 mmol) were added to a solution of 2- acid. { [(3,4-difluorophenyl) methyl] oxy} -5-formylbenzoic acid (can be prepared as described in the description 101; 1 g, 3.42 mmol) in N, N-dimethylformamide (25 ml), and the mixture was stirred at room temperature. The?,? - dimethylformamide was evaporated under reduced pressure and the residue was diluted with ethyl acetate (100 ml). The organic layer was washed with saturated sodium bicarbonate (2 x 50 mL) and water (2 x 50 mL). The organic layer was dried (MgSO 4), filtered and evaporated under reduced pressure to give the title compound as a yellow solid. 1.19 g.
MS (electrospray): m / z [M + H] + 370 EXAMPLE 81 5-Bromo-2- (f (2,4-difiuorophenyl) methynoxy) -fV-3-pyridinylbenzamide (E81) 3-Pyridhamine (0.21 g, 2.19 mmol), EDC (0.34 g, 1.75 mmol), HOBT (0.36 g, 2.33 mmol) and N-ethylmorpholine (0.37 mL, 2.91 mmol) were added to a solution of 5-bromo-2- acid. { [(2,4-difluorophenyl) methyl] oxy} benzoic acid (can be prepared by the description 103; 0.5 g, 1.46 mmole) in N, N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 4 hours. The?,? - dimethylformamide was removed on a Buchi rotoevaporator and the residue was diluted with ethyl acetate (50 ml) and washed with saturated aqueous sodium bicarbonate (1 x 25 ml) and water (1 x 25 ml) and dried (MgSO4), filtered and evaporated to give the title compound as a white solid. 0.6 g.
MS (electrospray): m / z [M + H] + = 420 EXAMPLE 82 2- (f (4-Fluorophenyl) methyl-oxo> -5-formyl-A / -3-pyridinylbenzamide (E82) 3-Pyridinamine (0.52 g, 5.47 mmol), EDC (0.84 g, 4.38 mmol), HOBT (0.89 g, 5.83 mmol) and N-ethylmorpholine (0.92 mL, 7.29 mmol) were added to a solution of 2- acid. { [(4-fluorophenyl) methyl] oxy} -5-formylbenzoic acid (can be prepared by the description 105; 1 g, 3.65 mmol) in N, N-dimethylformamide (25 ml), and the mixture was stirred at room temperature for 4 hr. The?,? - dimethylformamide was evaporated on a Buchi rotoevaporator. Saturated aqueous sodium bicarbonate (50 ml) and ethyl acetate (100 ml) were added to the residue and the mixture was stirred for 30 min. The organic compounds were separated and washed with water (50 ml), dried (MgSO 4) and evaporated under reduced pressure to give the title compound as a pale yellow solid. No further purification was carried out. 1.23 g.
MS (electrospray): m / z [M + H] + 351 EXAMPLE 83 2-fr (4-Fluorophenyl) methyloxy > -5-r (Z) - (hydroxyimino) methyl-1-A / -3-pyridinylbenzamide (E83) Pyridine (0.69 ml, 8.56 mmol) and hydroxylamine hydrochloride (1.19 mg, 1.71 mmol) were added to a solution of 2-. { [(4-fluorophenyl) methyl] oxy} -5-formyl-N-3-pyridinylbenzamide (can be prepared as described in Example 82; 300 mg, 0.86 mmol) in methanol (10 ml) and the mixture was stirred at room temperature for 30 min. The mixture was evaporated under reduced pressure to half its volume. The mixture was diluted with water (20 ml) and filtered. The solid was washed with cold water (20 ml) / cold methanol (5 ml) and dried under vacuum to give the title compound as a white solid. 220 mg.
MS (electrospray): m / z [M + H] + = 422 EXAMPLE 84 2- (f (4-Fluorophenyl) methyloxy) -5-formyl-A / -4-pyridazinylbenzamide (E84) 4-Pyridazinamine (0.52 g, 5.47 mmol), EDC (0.84 g, 4.38 mmol), HOBT (0.89 g, 5.83 mmol) and N-ethylmorpholine (0.92 ml, 7.29 mmol) were added to a solution of 2- . { [(4-fluorophenyl) methyl] oxy} -5-formylbenzoic acid (can be prepared by the description 105; 1 g, 3.65 mmol) in N, N-dimethylformamide (25 ml) and the mixture was stirred at room temperature for 4 hr. The?,? - dimethylformamide was evaporated under reduced pressure in a Buchi rotoevaporator. Saturated aqueous sodium bicarbonate (50 ml) and ethyl acetate (100 ml) were added to the residue and the mixture was stirred for 30 min. The organic compounds were separated and washed with water (50 ml), dried (MgSO 4) and evaporated under reduced pressure to give the title compound as a pale yellow solid. Without additional purification. No further purification was carried out. 0.98 g.
MS (electrospray): m / z [M + H] + = 352 EXAMPLE 85 2-. { r (3,4-Difluorophenyl) methyloxy > -5-r (Z) - (hydroxyimino) methyl- / tf-3-pyridinylbenzamide (E85) Pyridine (0.44 ml, 5.43 mmol) and hydroxylamine hydrochloride (75 mg, 1.09 mmol) were added to a solution of 2-. { [(3,4-difluorophenyl) methyl] oxy} -5-formyl-N-3-pyridinylbenzamide (can be prepared by the example 80, 200 mg, 0.54 mmol) in methanol (10 ml), and the mixture was stirred at room temperature for 30 min. The mixture was evaporated under reduced pressure to half its volume. The mixture was diluted with water (20 ml) and filtered. The solid was washed with water (20 ml) / methanol (5 ml) and dried with air under vacuum to give the title compound as a white solid. 67 mg.
MS (electrospray): m / z [M + H] + = 384 EXAMPLE 86 (-f (Phenylmethyl oxn-3-f (3-pyridinylamino) carboninphenyl) methyl) carbamate methyl (E86) HCI 2N (2 ml) and zinc (152 mg, 2.33 mmol) were added to a suspension of 5 - [(E / Z) - (hydroxyimino) methyl] -2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in Example 67; 81 mg, 0.23 mmol) in tetrahydrofuran (5 mL). The mixture was heated at 60 ° C for 15 minutes. The mixture was cooled and saturated NaHCO3 solution was added to adjust the pH to 10. Methyl chloroformate (0.22 ml, 2.80 mmol) was added and the pH was adjusted to pH 9-10 using saturated NaHCO3 solution. The mixture was stirred for one hour and then the tetrahydrofuran was removed under vacuum. The aqueous layer was extracted with ethyl acetate (2 x 10 mL), dried (MgSO4) and the solvent removed under vacuum to give an oil which was purified by MDAP to give the title compound as a white solid. 20 mg.
MS (electrospray): m / z [M + H] + = 392 1 H NMR (DMSO-c / 6): 3.54 (3 H, s), 4.17 (2 H, d, J = 6.14 Hz), 5.24 (2 H, s), 7.25 (1 H, d, J = 8.55 Hz ), 7.28-7.44 (5 H, m), 7.53 (2 H, d, J = 6.36 Hz), 7.59 (1 H, d, J = 2.19 Hz), 7.68-7.76 (1 H, m), 8.05- 8.12 (1 H, m), 8.27 (1 H, dd, J = 4.71, 1.42 Hz), 8.66 (1 H, d, J = 2.41 Hz), 10.35 (1 H, s) EXAMPLE 87 3- (4-f (Phenylmethyl) oxy-3-f (3-pyridinylamino) carboninphenyl) propanoate ethyl (E87) Cesium carbonate (171 mg, 0.53 mmol) and benzyl bromide (0.05 ml, 0.42 mmol) were added to a solution of 3-. { 4-hydroxy-3 - [(3-pyridinylammon) carbonyl] phenyl} ethyl propanoate (can be prepared as described in the description 98; 1 10 mg, 0.35 mmol) in N, N-dimethylformamide (10 ml). The mixture was stirred for one hour and then ethyl acetate (10 ml) and water (10 ml) were added. The organic layer was separated, washed further with water (3 x 10 mL), dried (MgSO) and the solvent removed under vacuum to give the title compound as a yellow solid. 126 mg.
MS (electrospray): m / z [M + H] + = 405 1 H NMR (DMSO-d 6): 1.07-1.26 (3 H, m), 2.57-2.70 (2 H, m), 2.79-2.97 (2 H, m), 3.96-4.13 (2 H, m), 5.22 ( 2 H, s), 7.08-7.61 (9 H, m), 8.00-8.15 (1 H, m), 8.27 (1 H, dd, J = 4.71, 1.42 Hz), 8.66 (1 H, d, J = 2.41 Hz), 10.33 (1 H, s) EXAMPLE 88 Acid 3-. { 4 - [(Phenylmethyl) oxn-3-r (3-pyridinylamino) carbonylphenyl) propanoic (E881 Lithium hydroxide (9.24 mg, 0.39 mmol) was added to a solution of 3-. { 4 - [(phenylmethyl) oxy] -3 - [(3-pyridinylamino) carbonyl] phenyl} ethyl propanoate (can be prepared as described in Example 87; 52 mg, 0.13 mmol) in tetrahydrofuran (2 mL) and water (0.5 mL) and the mixture was stirred overnight. The reaction mixture was purified by MDAP to give the title compound as a golden colored solid. 62 mg.
MS (electrospray): m / z [M + H] + = 377 1 H NMR (DMSO-d 6): 2.53-2.59 (2 H, m), 2.82 (2 H, t, J = 7.34 Hz), .22 (2 H, s), 7.21 (1 H, d, J = 8.55 Hz), 7.28-7.45 (5 H, m), 7.50-7.60 (3 H, m), 8.09 (1 H, br. .), 8.26 (1 H, d, J = 3.73 Hz), 8.66 (1 H, s), 10.32 (1 H, s) EXAMPLE 89 2- (1 (4-Fluorophenyl) methyloxy) -N-4-pyridazinyl-5- (4-pyridinyl) benzamide (E89) 4-Pyridinylboronic acid (81 mg, 0.66 mmol), sodium carbonate (1.09 ml, 1.09 mmol) and tetrakis (triphenylphosphino) palladium (0) (37.9 mg, 0.03 mmol) were added to a solution of 5-bromo-2- . { [. { 4-fluorophenyl) methylal] oxy} -? - 4-pyridazinylbenzamide (can be prepared as described in example 77; 220 mg, 0.55 mmole) in 1,2-dimethoxyethane (5 ml). The reaction was heated at 120 ° C for one hour. The solvent was removed under vacuum, redissolved in 1: 1 of dimethyl sulfoxide / methanol and purified by MDAP to give the title compound as a white solid. 58 mg.
MS (electrospray): m / z [M + H] + = 401 1 H NMR (DMSO-c / 6): 5.30 (2 H, s), 7.10-7.28 (2 H, m), 7.44 (1 H, d, J = 8.77 Hz), 7.57 (2 H, dd, J = 8.44, 5.59 Hz), 7.76 (2 H, d, J = 6.14 Hz), 7.96- 8.16 (3 H, m), 8.62 (2 H, d, J = 5.92 Hz), 9.08 (1 H, d, J = 5.70 Hz), 9.30 (1 H, d, J = 2.19 Hz), 10.90 (1 H, s) EXAMPLE 90 2- (f (4-Fluorophenyl) methyloxy> -N-3-pyridinyl-5- (4-pyridinyl) benzamide (E90) To a solution of 5-bromo-2-. { [. { 4-fluorophenyl) methyl] oxy} -N-3-pyridinylbenzamide (can be prepared as described in Example 59; 150 mg, 0.37 mmol) in 1,2-dimethoxyethane (5 ml) was added 4-pyridinylboronic acid (68.9 mg, 0.561 mmol), carbonate sodium (198 mg, 1.87 mmol) and bis (triphenylphosphino) palladium chloride (ll) (15.74 mg, 0.02 mmol), followed by water (1 ml). The reaction was heated to 80 ° C overnight. The reaction mixture was then placed in a microwave flask with another 0.5 eq. of boronic acid and 5% catalyst and heated at 120 ° C for 25 minutes. The solvent was removed under vacuum, redissolved in 1: 1 DMSO / methanol and purified by MDAP to give the title compound as a white solid. 56 mg.
EM (electro-spray): m / z [M + H] + = 400 1 H NMR (DMSO-c / 6): 5.31 (2 H, s), 7.21 (2 H, t, J = 8.88 Hz), 7.42 (2 H, d, J = 8.77 Hz), 7.60 (2 H, dd , J = 8.44, 5.59 Hz), 7.71-7.80 (2 H, m), 7.94-8.24 (4 H, m), 8.30 (1 H, dd, J = 4.71, 1.43 Hz), 8.56-8.65 (2 H , m), 8.76 (1 H, d, J = 2.41 Hz), 10.47 (1 H, s) EXAMPLE 91 2- (f (4-Fluorophenyl) methoxy> -5- (1H-pyrazol-4-yl) -N-3-pyridinylbenzamide (E91) 4- (4,4,5,5-Tetramethyl-1,3,3-dioxaborolan-2-yl) -1 H-pyrazole-1-carboxylic acid 1,1-dimethylethyl ester (141 mg, 0.48 mmol), sodium carbonate ( 0.87 ml, 0.87 mmol) and Pd (Ph3P) 4 (30.2 mg, 0.03 mmol) were added to a solution of 5-bromo-2-. { [(4-fluorophenyl) methyl] oxy} -N-3-pyridinylbenzamide (can be prepared as described in example 59; 175 mg, 0.44 mmol) in 1,2-dimethoxyethane (5 ml). The reaction was heated at 120 ° C for one hour. The solvent was removed under vacuum, triturated with 1: 1 DMSO / methanol and washed with methanol (10 mL) and ethyl acetate (20 mL) to give a white solid (80 mg). Recrystallization with 1: 1 DMSO / hot ethyl acetate gave a white solid (45 mg). The filtrate was purified by MDAP to give a white solid (22 mg). The 2 lots were combined to give the title compound. 67 mg.
MS (electrospray): m / z [M + H] + = 389 H NMR (DMSO-G6): 5.23 (2 H, s), 7.11-7.43 (5 H, m), 7.58 (2 H, dd, J = 8.33, 5.70 Hz), 7.86 (2 H, d, J = 2.19 Hz), 8.03-8.36 (3 H, m), 8.73 (1 H, d, J = 2 41 Hz), 10.39 (1 H, s), 12.91 (1 H, br. S.) EXAMPLE 92 2-. { f (4-Fluorophenyl) methyloxy) -5- (1H-pyrazol-4-yl) -N-4-pyridazinylbenzamide (E92) 4- (4,4,5,5-Tetramethyl-1, 3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylic acid 1,1-dimethylethyl ester (110 mg, 0.37 mmol), sodium carbonate (0.75 ml, 0.75 mmol) and tetrakis (triphenylphosphino) palladium (0) (25.9 mg, 0.02 mmol) were added to a solution of 5-bromo-2-. { [(4-fluorophenyl) methyl] oxy} -? - 4-pyridazinylbenzamide (can be prepared as described in example 77; 150 mg, 0.37 mmole) in 1,2-dimethoxyethane (5 ml). The reaction was heated at 120 ° C for one hour. The solvent was removed under vacuum, triturated with 1: 1 DMSO / methanol and washed with methane! (1 ml) and ethyl acetate (2 ml) to give a white solid. Recrystallization with 1: 1 DMSO / hot ethyl acetate gave the title compound as a white solid. 48.6 mg.
MS (electroaspersion): m / z [M + H] + = 390 H NMR (DMSO-c / 6): 5.09-5.29 (2 H, s), 7.08-7.23 (2 H, m), 7.29 (1 H, d, J = 8.77 Hz), 7.55 (2 H, dd, J = 8.66, 5.59 Hz), 7.71-7.88 (2 H, m), 7.94-8.15 (3 H, m), 9.06 (1 H, d, J = 5.70 Hz), 9.28 (1 H, d, J = 2.19 Hz), 10.83 (1 H, br s), 12.92 (1 H, br. S.) EXAMPLE 93 2- (r (4-Fluorophenyl) methyloxy) -5- (1-methyl-1 H -pyrazol-4-yn-N-3-pyridinylbenzamide (E93) 1-Methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H-pyrazole (78 mg, 0.37 mmol), 1 M sodium carbonate (0.75 ml) , 0.75 mmole) and tetrakis (triphenylphosphino) palladium (0) (25.9 mg, 0.02 mmole) were added to a solution of 5-bromo-2-. { [(4-fluorophenyl) methyl] oxy} -N-3-pyridinylbenzamide (can be prepared as described in example 59; 150 mg, 0.37 mmole) in 1,2-dimethoxyethane (4 ml). The reaction was heated at 120 ° C for one hour. The solvent was removed under vacuum to give a residue. Purification by MDAP gave the title compound as a white solid. 70 mg.
MS (electrospray): m / z [M + H] + = 403 1 H NMR (DMSO-d 6): 3.85 (3 H, s), 5.23 (2 H, br s), 7.00-7.43 (4 H, m), 7.49-7.94 (5 H, m), 8.15 (2 H, br. S.), 8.29 (1 H, br. S.), 8.73 (1 H, br. S.), 10.41 ( 1 H, br. S.) EXAMPLE 94 2- (r (4-Fluorophenyl) methyloxy) -5- (1-methyl-1 H -pyrazol-4-yl) -N-4-pyridazinylbenzamide (E94) 1 - . 1 -Methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H-pyrazole (78 mg, 0.37 mmol), 1 M sodium carbonate (0.75 ml) , 0.75 mmole) and tetrakis (triphenylphosphino) palladium (0) (25.9 mg, 0.02 mmole) were added to a solution of 5-bromo-2-. { [(4-fluorophenyl) methyl] oxy} -N-4-pyridazinylbenzamide (can be prepared as described in Example 77; 150 mg, 0.37 mmol) in 1,2-dimethoxyethane (4 mL). The reaction was heated at 120 ° C for one hour. The solvent was removed under vacuum to give a residue. Purification by MDAP gave the title compound as a white solid. 50 mg.
EM (electroaspersion): m / z [M + H] + = 404 1 H NMR (DMSO-c / 6): 3.85 (3 H, s), 5.22 (2 H, br. S.), 7.08-7.36 (3 H, m), 7.56 (2 H, d, J = 6.14 Hz), 7.68-7.92 (3 H, m), 8.04 (1 H, br. S.), 8.16 (1 H, s), 9.07 (1 H, d, J = 5.70 Hz), 9.28 (1 H, br. S.), 10.84 (1 H, br. S.) EXAMPLE 95 2- (r 4-Fluorophenyl) methyloxy -5- (1-methyl-1 H -pyrazol-5-yl) -N-3-pyridinylbenzamide (E95) Acid (1-methyl-1 H -pyrazol-5-yl) boronic acid (30.1 mg, 0.24 mmol), sodium carbonate (0.40 ml, 0.40 mmol) and tetrakis (triphenylphosphino) palladium (0) (13.82 mg, 0.01 mmol) they were added to a solution of 5-bromo-2-. { [(4-fluorophenyl) methyl] oxy} -N-3-pyridinylbenzamide (can be prepared as described in example 59; 80 mg, 0.20 mmol) in 1,2-dimethoxyethane (3 ml). The mixture was heated at 120 ° C for 1 hour. The solvent was removed under vacuum and purified by MDAP to give the title compound as a brown gum. 13 mg.
MS (electrospray): m / z [M + H] + = 403 1 H NMR (DMSO-d 6): 3.86 (3 H, s), 5.29 (2 H, s), 6.42 (1 H, d, J = 1.75 Hz), 7.14-7.28 (2 H, m), 7.33-7.43 (2 H, m), 7.46 (1 H, d, J = 1.75 Hz), 7.60 (2 H, dd, .7 = 8.55, 5.70 Hz), 7.69 (1 H, dd, J = 8.55, 2.41 Hz), 7.75 (1 H, d, J = 2.41 Hz), 8.04-8.18 (1 H, m), 8.29 (1 H, dd, J = 4.60, 1.32 Hz), 8.73 (1 H, d, J = 2.41 Hz), 10.42 (1 H, s) EXAMPLE 96 5- (1-Methyl-1 H -pyrazol-5-yl) -2 - [(phenylmethyl) oxyl-A / -3-pyridinylbenzamide (E96) To a microwave flask was added 5-bromo-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in example 2; 100 mg, 0.26 mmol), 1-methyl-5- ( 4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H-pyrazole (59.7 mg, 0.29 mmol), 1,2-dimethoxyethane (2 mL), 1 M sodium carbonate (0.52 ml, 0.52 mmol) and tetrakis (triphenylphosphino) palladium (0) (18.09 mg, 0.02 mmol). The flask was sealed and heated at 120 ° C for 25 min under microwave conditions. The mixture was evaporated and water (5 ml) was added to the residue, the mixture was extracted with ethyl acetate (3 x 10 ml). The organic compounds were combined and evaporated under vacuum and the residue was purified using MDAP to give the title compound. 22 mg.
EM (electroaspersion): m / z [M + H] + = 385 1 H NMR (400 MHz, CHLOROFORM-d) 3.93 (3 H, s), 5.30 (2 H, s), 6.35 (1 H, d, J = 1.75 Hz), 7.15-7.34 (2 H, m), 7.45 -7.68 (7 H, m), 7.97 (1 H, br. S.), 8.14 (1 H, d, J = 8.33 Hz), 8.24-8.34 (1 H, m), 8.42 (1 H, d, J = 2.41 Hz), 10.03 (1 H. s) EXAMPLE 97 5- (1-Methyl-1H-pyrazol- -yl) -2-r (phenylmethyl) oxyl-A / -3-pyridinylbenzamide (E97) To a microwave flask was added 5-bromo-2- [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in example 2; 100 mg, 0.26 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -H-pyrazole (59.7 mg, 0.29 mmol), 1,2-dimethoxyethane (2 mL), 1 M sodium carbonate (0.52 ml, 0.52 mmol) and tetrakis (triphenylphosphino) palladium (0) (18.09 mg, 0.02 mmol). The flask was sealed and heated at 120 ° C for 25 min under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3 x 10 ml). The organic compounds were combined and evaporated and the residue was purified using MDAP to give the title compound. 31 mg.
MS (electrospray): m / z [M + H] + = 385 1 H NMR (400 MHz, CHLOROFORM-d) 3.95 (3 H, s), 5.25 (2 H, s), 7.10-7.24 (2 H, m), 7.44-7.59 (5 H, m), 7.59-7.71 ( 2 H, m), 7.79 (1 H, s), 8.00 (1 H, d, J = 1.97 Hz), 8.12 (1 H, d, J = 8.55 Hz), 8.27 (1 H, d, J = 3.95 Hz), 8.41 (1 H, d, J = 2.41 Hz), 10.09 (1 H, s) EXAMPLE 98 5-Bromo-A / - (5-fluoro-3-pyridinyl-2-r (phenylmethyl) oxy-1-benzamide (E98) Diisopropylethylamine (0.28 ml, 1.63 mmol), 5-fluoro-3-pyridinamine (73.0 mg, 0.65 mmol) and HATU (371 mg, 0.98 mmol) were added to a solution of 5-bromo-2- [(phenylmethyl) oxy] ] benzoic acid (can be prepared as described in the description 5; 200 mg, 0.651 mmol) in N, N-dimethylformamide (50 ml) at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was then purified by chromatography on silica using 0-100% ethyl acetate / hexane. However, a number of impurities persisted and the residue was repurified by MDAP to give the title compound. 45 mg.
MS (electrospray): m / z [M + H] + = 402 1 H NMR (400 MHz, CHLOROFORM-d) 5.22 (2 H, s) 7.07 (1 H, d, J = 8.77 Hz) 7.47-7.62 (6 H, m) 7.65 (1 H, dd, J = 8.77, 2.63 Hz) 8.07 (1 H, d, J = 10.74 Hz) 8.14 (1 H, br. S.) 8.43 (1 H, d, J = 2.63 Hz) 10.08 (1 H, br. S.) EXAMPLE 99 2-r (Phenylmethyl) oxy-1-5- (1H-pyrazol-4-yl) -A / -3-pyridinylbenzamide (E99) To a microwave flask was added 5-bromo-2 - [(phenylmethyl) oxy] -? - 3-pyridinylbenzamide (can be prepared as described in Example 2, 310 mg, 0.81 mmol), 4- (4.4, 5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H-pyrazole-1-carboxylic acid 1,1-dimethylethyl ester (262 mg, 0.89 mmol), 1,4-dioxane (3 mi), sodium carbonate (1.62 ml, 1.62 mmol) and tetrakis (triphenylphosphino) palladium (0) (56.1 mg, 0.05 mmol). The flask was sealed and heated at 120 ° C for 25 min under microwave conditions. The mixture was evaporated under reduced pressure and water (5 ml) was added to the residue. The mixture was extracted with ethyl acetate (3 x 10 ml). The organics were combined and evaporated under reduced pressure, and the residue was purified using MDAP to give the title compound. 44 mg.
MS (electrospray): m / z [M + H] + = 371 H NMR (400 MHz, DMSO-c / 6) 5.26 (2 H, s), 7.24-7.43 (5 H, m), .52 (2 H, s), 7.66-7.82 (1 H, m), 7.87. (2 H, d, J = 2.41 Hz), 8.03-8.15 (1 H, m), 8.13-8.25 (1 H, m), 8.23-8.36 (1 H, m), 8.61-8.81 (1 H, m ), 10.31-10.48 (1 H, m), 12.76-13.08 (1 H, m).
EXAMPLE 100 2-r (Phenylmethyl) oxn- / V-3-pyridinyl-5- (4-pyridinyl) benzamide (E100) microwave flask was added 5-bromo-2- [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in example 2; 200 mg, 0.52 mmol), 1,4-dioxane (2 ml) , 4-pyridinylboronic acid (64.1 mg, 0.52 mmole), 1 M sodium carbonate (1.04 ml, 1.04 mmol) and tetrakis (triphenylphosphino) palladium (0) (36.2 mg, 0.03 mmol). The flask was sealed and heated to 100X for 30 min under microwave conditions. The mixture was evaporated under reduced pressure and the residue was purified using MDAP to give the title compound. 41 mg.
MS (electrospray): m / z [M + H] + = 382 H NMR (400 MHz, CHLOROFORM-d) 5.32 (2 H, s), 7.23 (1 H, d, J = 4.82 Hz), 7.30 (1 H, d, J = 8.55 Hz), 7.51-7.62 (7 H , m), 7.85 (1 H, dd, J = 8.55, 2.41 Hz), 7.99 (1 H, d, J = 2.63 Hz), 8.11-8.18 (1 H, m), 8.29 (1 H, dd, J = 4.71, 1.43 Hz), 8.63- 8.75 (3 H, m), 10.04 (1 H. s).
EXAMPLE 101 2-r (Phenylmethyl) oxy-A /, 5-di-3-pyridinylbenzamide (E101) To a microwave flask was added 5-bromo-2- [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in example 2; 200 mg, 0.52 mmol), 1,4-dioxane (2 mi), 1 M sodium carbonate (1.04 ml, 1.04 mmol), 3- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) pyridine (107 mg, 0.52 mmol) and tetrakis (triphenylphosphino) palladium (0) (36.2 mg, 0.03 mmol). The flask was sealed and heated at 100 ° C for 30 min under microwave conditions. The mixture was evaporated under reduced pressure and the residue was purified using MDAP. Some impurities persisted and the mixture was repurified using MDAP to give the title compound. 17 mg.
MS (electrospray): m / z [M + H] + = 382 1 H NMR (400 MHz, CHLOROFORM-d) 5.30 (2 H, S), 7.23 (1 H, dd, J = 8.44, 4.71 Hz), 7.25-7.33 (1 H, m), 7.40 (1 H, dd, J = 7.78, 4.71 Hz), 7.49- 7.62 (5 H, m), 7.78 (1 H, dd, J = 8.55, 2.41 Hz), 7.96 (1 H, dt, J = 8.06, 1.89 Hz), 8.01 (1 H, d, J = 2.41 Hz), 8.14 (1 H, dt, J = 8.44, 1.92 Hz), 8.29 (1 H, dd, J = 4.60, 1.32 Hz), 8.53- 8.67 (2 H, m), 8.89 (1 H, d, J = 1.75 Hz), 10.07 (1 H, s).
EXAMPLE 102 A / - (5-Fluoro-3-pyridinyl) -2-r (phenylmethyl) oxn-5- (4-pyridinyl) benzamide (E102) To a microwave flask was added 5-bromo-N- (5-fluoro-3-pyridinyl) -2 - [(phenylmethyl) oxy] benzamide (can be prepared as described in example 98; 200 mg, 0.50 mmol) , 1,4-dioxane (2 ml), 4-pyridinylboronic acid (73.5 mg, 0.60 mmol), 1 M sodium carbonate (1.00 ml, 1.00 mmol) and tetrakis (triphenylphosphino) palladium (0) (34.6 mg, 0.03 mmoles). The flask was sealed and heated at 130 ° C for 30 min under microwave conditions. The mixture was evaporated under reduced pressure and the residue was purified using MDAP (twice) to give the title compound. 9 mg.
MS (electrospray): m / z [M + H] + = 400 1 H NMR (400 MHz, CHLOROFOR Od) 5.32 (2 H, s), 7.33 (1 H, d, J = 8.55 Hz), 7.54-7.60 (5 H, m), 7.62 (1 H, s), 7.67 ( 2 H, d, J = 6.14 Hz), 7.89 (1 H, dd, J = 8.55, 2.63 Hz), 8.1 1 (1 H, dd, J = 10.74, 2. 9 Hz), 8.16 (1 H, d , J = 2.63 Hz), 8.64-8.78 (3 H, m), 10.16 (1 H, s).
EXAMPLE 103 2-α (Phenylmethyl) oxy-1-A-3-pyridinyl-5-r (3 5S) -3,4,5-trimethyl-1-piperazinylbenzamide (E103) (2R, 6S) -1, 2,6-Trimethylpiperazine (105 mg, 0.52 mmol), cesium carbonate (680 mg, 2.09 mmol), BINAP (2.44 mg, 3.91 pmol) and Pd2 (dba) 3 (1 20 mg, 1.30 pmoles) were added to 5-bromo-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in example 2; 200 mg, 0.52 mmole) in anhydrous toluene ( 5 ml), and the mixture was heated to reflux overnight. The reaction mixture was evaporated under reduced pressure.
Water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic compounds were combined and evaporated and the residue was purified by MDAP twice to give the title compound. 180 mg.
MS (electrospray): m / z [M + H] + = 431 H NMR (400 Hz, METANOL-d4) 1.37 (6 H, d, J = 6.36 Hz), 2.72 (3 H, s), 2.79 (2 H, t, J = 1 1.95 Hz), 3.13 (2 H, br. s.), 3.64 (2 H, d, J = 12.50 Hz), 5.22 (2 H, s), 7.24 (2 H, s), 7.32 (1 H, dd, J = 8.00, 4.71 Hz), 7.37-7.47 (3 H, m), 7.48-7.57 (2 H, m), 7.92 (1 H, d, J = 8.33 Hz), 8.22 (1 H, br. S.), 8.38 (1 H, br .s.), 8.50-8.78 (1 H, m), 8.51- 8.86 (1 H, m).
EXAMPLE 104 5- (2-Fluoro-4-pyridinyl) -2-f (phenylmethyl) oxn-A / -3-pyridinylbenzamide (E104) (2-Fluoro-4-pyridinyl) boronic acid (425 mg, 3.02 mmol), bis (triphenylphosphino) palladium (II) chloride (70.6 mg, 0.10 mmol) and sodium carbonate (1066 mg, 10.06 mmol) as a solution in 2 ml of water was added to a solution of 5-bromo-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in Example 2; 771 mg, 2.01 mmol) in 1,2-dimethoxyethane (20 mL). The mixture was refluxed for 2 hours. The mixture was diluted with ethyl acetate (50 ml) and water (50 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The organic compounds were combined and evaporated. The residue was purified by chromatography on silica eluting with 0-0% methanol / dichloromethane, 1% ammonia, to give the title compound as an off-white solid. 500 mg.
MS (electrospray): m / z [M + H] + = 400 1H RN (400 MHz, CHLOROFORM-d) 5.36 (2 H, s), 7.18-7.32 (2 H, m), 7.32-7.44 (2 H, m), 7.49-7.66 (6 H, m), 7.89 ( 1 H, dd, J = 8.55, 2.19 Hz), 8.01 (1 H, d, J = 7.45 Hz), 8.12 (1 H, d, J = 1.53 Hz), 8.25 (2 H, t, J = 5.04 Hz ), 8.60 (1 H, d, J = 2.19 Hz).
EXAMPLE 105 2- (r (3,4-Difluorophenyl) methyloxy> -5- (1-methyl-1H-pyrazol-4-yl) - / V-4-pyridazinylbenzamide (E105) 5-Bromo-2- was added to a microwave flask. { [(3,4-difluorophenyl) methyl] oxy} -N-4-pyridazinylbenzamide (can be prepared by Example 78; 150 mg, 0.36 mmole), 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dloxaborolan-2-yl) ) -1 H-pyrazole (75 mg, 0.36 mmol), 1,2-dimethoxyethane (2 mL), 1 M sodium carbonate (0.71 mL, 0.71 mmol), and tetrakis (triphenylphosphino) palladium (0) (24.75 mg, 0.02 mmol). The bottle was sealed and heated at 120 ° C for 1 hour under microwave conditions. The mixture was evaporated under reduced pressure and water (5 ml) was added to the residue. The mixture was extracted with ethyl acetate (3 x 10 mL). The organic compounds were combined and evaporated and the residue was purified using MDAP to give the title compound. 80 mg.
MS (electrospray): m / z [M + H] + = 422 1 H NMR (400 MHz, DMSO-c 6) 3.85 (3 H, s), 5.23 (2 H, s), 7.27 (1 H, d, J = 8.77 Hz), 7.35 (1 H, d, J = 5.26 Hz), 7.41 (1 H, dd, J = 10.74, 8.33 Hz), 7.57 (1 H, ddd, J = 1 1.56, 7.95, 1.75 Hz), 7.73 (1 H, dd, J = 8.55, 2.41 Hz), 7.80 (1 H, d, J = 2.41 Hz), 7.87 (1 H, s), 8.05 (1 H, dd , J = 5.92, 2.63 Hz), 8.15 (1 H, s), 9.08 (1 H, d), 9.32 (1 H, d, J = 1.97 Hz), 10.85 (1 H, br. S.).
EXAMPLE 106 2-U (3,4-Difluorofeninmetinoxi) -A / -4-pyridazinyl-5- (4-pyridinyl) benzamide (E106) 5-Bromo-2- was added to a microwave flask. { [(3,4-difluorophenyl) methyl] oxy} -N-4-pyridazinylbenzamide (can be prepared as described in example 78; 200 mg, 0.48 mmole), 4-pyridinylboronic acid (88 mg, 0.74 mmole), tetrakis (triphenylphosphino) palladium (0) (33.0 mg, 0.03 mmoles), sodium carbonate (0.95 ml, 0.95 mmol) and 1,2-dimethoxyethane (3 ml). The mixture was sealed and heated at 120 ° C for 1 hour under microwave conditions. The 1,2-dimethoxyethane was evaporated under reduced pressure and the residue was purified using MDAP to give the title compound. 35 mg.
MS (electrospray): m / z [M + H] + = 419 1 H NMR (400 MHz, DMSO-d 6) 5.30 (2 H, s), 7.32-7.50 (3 H, m), .55-7.67 (1 H, m), 7.74-7.86 (2 H, m), 7.95 -8.15 (3 H, m), 8.48-8.73 (2 H, m), .09 (1 H, d, J = 5.92 Hz), 9.34 (1 H, d, J = 1.75 Hz), 10.95 (1 H , s).
EXAMPLE 107 2- (f (3,4-Difluorophenyl) methoxy> -5- (1H-pyrazol-5-yl) - / V-3-pyridinylbenzamide (E107) 5-Bromo-2- was added to a microwave flask. { [(3,4-difluorophenyl) methyl) oxy} -N-3-pyridinylbenzamide (can be prepared as described in example 60; 120 mg, 0.29 mmol), 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H -pyrazole-1-carboxylate 1,1-dimethylethyl ester ( 93 mg, 0.32 mmol), 1,2-dimethoxyethane (2 mL), 1 M sodium carbonate (0.57 mL, 0.57 mmol) and tetrakis (triphenylphosphino) palladium (0) (19.85 mg, 0.02 mmol). The vial was sealed and heated at 20 ° C for 25 min under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3 x 10 ml). The organic compounds were combined, evaporated under reduced pressure and the residue was purified using MDAP to give the title compound. 65 mg.
MS (electrospray): m / z [M + H] + = 407 1 H NMR (400 MHz, DMSO-d 6) 5.23 (2 H, s), 7.24 (1 H, d, J = 8.55 Hz), 7.33-7.48 (3 H, m), 7.54-7.66 (1 H, m) , 7.74 (1 H, dd, J = 8.55, 2.41 Hz), 7.84 (1 H, d, J = 2.9 Hz), 7.88-8.01 (1 H, m), 8.12-8.26 (2 H, m) , 8.29 (1 H, dd, J = 4.60, 1.32 Hz), 8.79 (1 H, d, J = 2.19 Hz), 10.42 (1 H, s), 12.79- 13.07 (1 H, m).
EXAMPLE 108 2- (r (3,4-Difluorophenyl) methyloxy) -5- (1H-pyrazol-4-yl) -A / -4- pyridazinylbenzamide (E108) 5-Bromo-2- was added to a microwave flask. { [(3,4-difluorophenyl) methyl] oxy} -N-4-pyridazinylbenzamide (can be prepared as described in example 78; 150 mg, 0.36 mmole), 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2 il) -1 H-pyrazole-1-carboxylic acid 1,1-dimethylethyl ester (16 mg, 0.39 mmol), 1,2-dimethoxyethane (2 mL), 1 M sodium carbonate (0.71 mL, 0.71 mmol) and tetrakis (triphenylphosphino) palladium (0) (24.75 mg, 0.02 mmol). The flask was sealed and heated at 120 ° C for 25 min under microwave conditions. The mixture was evaporated under reduced pressure. Water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (30 mL). The organics were combined and evaporated under reduced pressure and the residue was purified using MDAP to give the title compound. 41 mg.
MS (electrospray): m / z [M + H] + = 408 1 H NMR (400 MHz, DMSO-d 6) 5.23 (2 H, s), 7.27 (1 H, d, J = 8.55 Hz), 7.35 (1 H, br. S.), 7.38-7.49 (1 H, m ), 7.53-7.63 (1 H, m), 7.78 (1 H, dd, J = 8.66, 2.30 Hz), 7.84 (1 H, d, J = 2.19 Hz), 8.06 (3 H, m), 9.08 ( 1 H, d, J = 5 92 Hz), 9.33 (1 H, d, J = 1.97 Hz), 10.73-11.06 (1 H, m), 12.62- 13.26 (1 H, m).
EXAMPLE 109 2-. { r (3,4-Difluorophenyl) methyloxy > -A / -3-pyridinyl-5- (4-pyridinyl) benzamide (E109) 5-Bromo-2- was added to a microwave flask. { [(3,4-difluorophenyl) methyl] oxy} -N-3-pyridinylbenzamide (can be prepared as described in example 60; 120 mg, 0.29 mmol), 4-pyridinylboronic acid (52.8 mg, 0.43 mmol), tetrakis (triphenylphosphino) palladium (0) (19.85 mg, 0.02 mmoles), sodium carbonate (0.57 ml, 0.57 mmol) and 1,2-dimethoxyethane (3 ml). The mixture was sealed and heated at 120 ° C for 1 hr under microwave conditions. The 1,2-dimethoxyethane was evaporated under reduced pressure and the residue was purified using MDAP to give the title compound. 23.5 mg.
MS (electrospray): m / z [M + H] + = 418 H NMR (400 MHz, METHANOL-d4) 5.32 (2 H, s), 7.23-7.45 (4 H, m), 7.45-7.55 (1 H, m), 7.69-7.78 (2 H, m), 7.96 ( 1 H, dd, J = 8.66, 2.52 Hz), 8.15 (1 H, dd, J = 8.33, 0.88 Hz), 8.23-8.32 (2 H, m), 8.32-8.45 (1 H, m), 8.57 ( 2 H, d, J = 6.14 Hz), 8.64 (1 H, d, J = 2.19 Hz).
EXAMPLE 110 2- (r (3,4-Difluorophenyl) methyloxy> -5- (1-methyl-1H-pyrazol-4-yl) -A / -3- pyridinylbenzamide (E110) 5-Bromo-2- was added to a microwave flask. { [(3,4-difluorophenyl) methyl] oxy} -N-3-pyridinylbenzamide (can be prepared as described in Example 60; 120 mg, 0.29 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2- dioxaborolan-2-yl) -1 H-pyrazole (65.5 mg, 0.32 mmol), 1,2-dimethoxyethane (2 mL), 1 M sodium carbonate (0.57 mL, 0.57 mmol) and tetrakis (triphenylphosphino) palladium (0) (9.85 mg, 0.017 mmol). The vial was sealed and heated at 120 ° C for 1 hr under microwave conditions. The mixture was evaporated under reduced pressure. Water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate (30 mL). The organic compounds were combined, evaporated under reduced pressure and the residue was purified using the MDAP to give the title compound. 28 mg.
MS (electrospray): m / z [M + H] + = 421 H NMR (400 MHz, METHANOL-d4) 3.91 (3 H, s), 5.22 (2 H, s), 7.07-7.53 (6 H, m), 7.66 (1 H, dd, J = 8.66, 2.08 Hz) , 7.77 (1 H, s), 7.90 (1 H, s), 8.00 (1 H, d, J = 1.75 Hz), 8.05-8.16 (1 H, m), 8.26 (1 H, d, J = 3.95 Hz), 8.53-8.71 (1 H, m).
EXAMPLE 111 2- (I (3,4-Difluorophenyl) methyloxy) -5- (4-morpholinylmethyl) -A / -4- pyridazinylbenzamide (E111) Morpholine (0.05 ml, 0.54 mmol) and acetic acid (0.03 ml, 0.54 mmol) were added to a solution of 2-. { [(3,4-difluorophenyl) methyl] oxy} -5-formyl-N-4-pyridazinylbenzamide (can be prepared by example 79; 200 mg, 0.54 mmole) in DCE (5 ml), and the mixture was stirred at room temperature for 10 min. Then, sodium triacetoxyborohydride (172 mg, 0.81 mmol) was added and the mixture was stirred at 50 ° C overnight. Saturated sodium bicarbonate (10 mL) was added and the mixture was stirred for 10 min before being diluted with dichloromethane (25 mL). The organic layer was separated and the aqueous phase was extracted with dichloromethane (25 ml). The organic compounds were combined and evaporated under reduced pressure. The residue was purified by MDAP to give the title compound. 147 mg.
MS (electrospray): m / z [M + H] = 441 1 H NMR (400 MHz, DMSO-c / 6) 2.27-2.42 (4 H, m), 3.46 (2 H, s), 3.51-3.65 (4 H, m), 5.20 (2 H, s), 7.24 ( 1 H, d, J = 8.55 Hz), 7.31-7.52 (3 H, m), 7.53-7.66 (2 H, m), 8.03 (1 H, dd, J = 5.92, 2.63 Hz), 8.40 (1 H , s), 9.06 (1 H, dd, J = 5.92, 0.88 Hz), 9.23-9.35 (1 H, m).
EXAMPLE 112 2- (r (3,4-Difluorofeninmethyl-oxy) -5- (4-morpholinylmethyl) - / V-3-pyridinylbenzamide (E112) Morpholine (0.05 ml, 0.54 mmole) and acetic acid (0.03 ml, 0.54 mmole) were added to a solution of 2-. { [(3,4-difluorophenyl) methyl] oxy} -5-formyl-N-3-pyridinylbenzamide (can be prepared by the example 80; 200 mg, 0.54 mmol) in DCE (5 ml), and the mixture was stirred at room temperature for 10 min. Then, sodium triacetoxyborohydride (173 mg, 0.81 mmol) was added and the mixture was heated at 50 ° C overnight. Saturated sodium bicarbonate (10 ml) was added and the mixture was stirred for 10 min before being diluted with dichloromethane (25 ml) The organic layer was separated and the aqueous phase was extracted with dichloromethane (25 ml), the organic compounds were they combined and evaporated under reduced pressure. The residue was purified by MDAP to give the title compound. 82 mg.
MS (electrospray): m / z [M + H] + = 440 H NMR (400 MHz, DMSO-d6) 2.36 (4 H, d, J = 3.95 Hz), 3.46 (2 H, s), 3.50-3.68 (4 H, m), 5.21 (2 H, s), 7.22 (1 H, d, J = 8.33 Hz), 7.30-7.51 (4 H, m), 7.58 (2 H, d, J = 1.97 Hz), 8.04-8.17 (1 H, m), 8.28 (1 H, dd, J = 4.71, 1.42 Hz), 8.74 (1 H, d, J = 2.19 Hz), 10.33 (1 H, s).
EXAMPLE 113 2- (r (2-Cyanophenemethyloxy) -5- (1-methyl-1 H -pyrazol-4-yl) -A / -3- pyridinylbenzamide (E113) 5-Bromo-2- was added to a microwave flask. { [(2-cyanophenyl) methyl] oxy} -N-3-pyridinylbenzamide (can be prepared as described in Example 23; 172 mg, 0.42 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2) -yl) -1 H-pyrazole (96 mg, 0.46 mmol), 1,2-dimethoxyethane (2 mL), 1 M sodium carbonate (0.84 mL, 0.84 mmol) and tetrakis (tnphenylphosphino) palladium (0) (29.2 mg, 0.025 mmol). The vial was sealed and heated at 120 ° C for 1 hr under microwave conditions. The mixture was evaporated under reduced pressure. Water (5ml) was added to the residue and the mixture was extracted with ethyl acetate (3 x 10 mL). The organic compounds were combined, evaporated under reduced pressure and the residue was purified using MDAP to give the title compound. 58 mg.
MS (electrospray): m / z [M + H] + = 4 0 1 H NMR (400 MHz, DMSO-c / 6) 3.86 (3 H, s), 5.42 (2 H, s), 7.32 (2 H, d, J = 8.77 Hz), 7.55 (1 H, d, J = 1.10 Hz), 7.70 (2 H, dd, J = 4.28, 1.86 Hz), 7.77-7.84 (2 H, m), 7.85-7.92 (2 H, m), 8.06-8.12 (1 H, m), 8.16 ( 1 H, s), 8.28 (1 H, dd, J = 4.71, 1.43 Hz), 8.71 (1 H, d, J = 2.41 Hz), 10.35 (1 H, s).
EXAMPLE 114 2- (fr2- (Methyloxy) pheninmethyl> oxy) -5- (1-methyl-1H-pyrazol-4-yl) -A / -3- pyridinylbenzamide (E114) microwave flask was added 5-bromo-2- ( { [2- (methyloxy) phenyl] methyl} oxy!) -N-3-pyridinylbenzamide (can be prepared as described in Example 21; 1 15 mg, 0.28 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1, 3 , 2-dioxaborolan-2-yl) -1 H-pyrazole (63.7 mg, 0.31 mmol), 1,2-dimethoxyethane (2 mL), 1M sodium carbonate (0.56 mL, 0.56 mmol) and tetrakis (triphenylphosphino) palladium ( 0) (19.29 mg, 0.02 mmol). The vial was sealed and heated at 120 ° C for 1 hr under microwave conditions. The mixture was evaporated under reduced pressure. Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3 x 10 ml). The organic compounds were combined, evaporated under reduced pressure and the residue was purified using MDAP to give the title compound. 10 mg.
MS (electrospray): m / z [M + H] + = 415 1 H NMR (400 MHz, CHLOROFOR Od) 3.79 (3 H, s), 3.95 (3 H, s), 5.31 (2 H, s), 6.99-7.10 (2 H, m), 7.18-7.25 (2 H, m), 7.46 (2 H, dd, J = 7.67, 1.75 Hz), 7.60-7.69 (2 H, m), 7.79 (1 H, s), 8.04 (1 H, d, J = 2.63 Hz), 8.16 -8.23 (1 H, m,) 8.28 (1 H, dd, J = 4.82, 1.32 Hz), 8.39 (1 H, d, J = 2.41 Hz), 10.24 (1 H, s).
EXAMPLE 115 2 - ((f3- (Methyloxy) phenomethyl) oxy -5- (1-methyl-1H-pyrazole-4-in- / V-3-pyridinylbenzamide (E115) To a microwave flask was added 5-bromo-2- ( { [3- (methyloxy) phenyl] methyl.}. Oxy) -N-3-pyridinylbenzamide ((can be prepared as described in US Pat. Example 18; 120 mg, 0.29 mmol), 1-methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1H-pyrazole (66.5 mg, 0.32 mmol), 1, 2-dimethoxyethane (2 ml), 1 M sodium carbonate (0.58 ml, 0.58 mmol) and tetrakis (triphenylphosphino) palladium (0) (20.13 mg, 0.02 mmol) The flask was sealed and heated at 120 ° C for 1 hr under microwave conditions.The mixture was evaporated under reduced pressure.Water (5 ml) was added to the residue and the mixture was extracted with ethyl acetate (3 x 10 ml) .The organic compounds were combined were evaporated under reduced pressure and the residue was purified using MDAP to give the title compound 24 mg.
MS (electrospray): m / z [M + H] + = 415 H NMR (400 MHz, METHANOL-d4) 3.79 (3 H, s), 3.94 (3 H, s), 5. 25 (2 H, s), 7.01 (1 H, dd, J = 8.22, 2.08 Hz), 7.08-7.17 (2 H, m), 7.24 (1 H, d, J = 8.55 Hz), 7.31 (1 H , dd, J = 8.11, 4.82 Hz), 7.39 (1 H, t, J = 7.78 Hz), 7.64-7.72 (1 H, m), 7.78 (1 H, s), 7.83 (1 H, s), 7.96 (1 H, d, J = 8.33 Hz), 8.19-8.27 (2 H, m), 8.35 (1 H, s).
EXAMPLE 116 2-U (2,4-Difluorophenyl methyoxy) -5- (1-methyl-1H-pyrazol-4-yl) -A / -3- pyridinylbenzamide (E116) 1-Methyl-4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H-pyrazole (112 mg, 0.54 mmol), tetrakis (triphenylphosphino) palladium or (0) (24.81 mg, 0.02 mmol) and sodium carbonate (0.72 ml, 0.72 mmol) were added to a solution of 5-bromo-2-. { [(2,4-difluorophenyl) methyl] oxy} -N-3-pyridinylbenzamide (can be prepared by example 81; 150 mg, 0.36 mmol) in 1,2-dimethoxyethane (3 ml), and the mixture was heated at 120 ° C for 1 hr under microwave conditions. The mixture was evaporated under reduced pressure and the residue was purified by MDAP to give the title compound. 58 mg.
EM (electro-spray): m / z [M + H] + = 421 1 H NMR (400 MHz, METHANOL-d 4) 3.91 (3 H, s), 5.31 (2 H, s), 6.95-7.08 (2 H, m), 7.28 (1 H, d, J = 8.55 Hz), 7.37 (1 H, dd, J = 8.33, 4.82 Hz), 7.62 (1 H, d, J = 6.36 Hz), 7.69 (1 H, dd, J = 8.66, 2.30 Hz), 7.78 (1 H, s), 7.90 (1H, s), 8.02-8.11 (2 H, m), 8.25 (1 H, dd, J = 4.71, 1.21 Hz), 8.53 (1 H, d, J = 2.19 Hz).
EXAMPLE 117 2- (r (4-Fluorophenyl) methyloxy) -5- (4-morpholinyl-1-methyl) - / V-3-pyridinylbenzamide (E117) Morpholine (0.05 ml, 0.57 mmole) and acetic acid (0.03 ml, 0.57 mmole) were added to a solution of 2-. { [(4-fluorophenyl) methyl] oxy} -5-formyl-N-3-pyridinylbenzamide (can be prepared by example 82; 200 mg, 0.57 mmol) in DCE (5 ml) and the mixture was stirred at room temperature for 10 min. Then, sodium triacetoxyborohydride (181 mg, 0.86 mmol) was added and the mixture was heated at 50 ° C overnight. Saturated sodium bicarbonate (10 ml) was added and the mixture was stirred for 10 min before being diluted with dichloromethane (25 ml). The organic layer was separated and the phase aqueous was extracted with dichloromethane (25 ml). The organic compounds were combined and evaporated under reduced pressure. The residue was purified by MDAP to give the title compound. 150 mg.
MS (electrospray): m / z [M + H] + = 422 1 H NMR (400 MHz, METHANOL-d 4) 2.40-2.56 (4 H, m), 3.56 (2 H, s), 3.64-3.77 (4 H, m), 5.28 (2 H, s), 7.15 (2 H , t, J = 8.77 Hz), 7.29 (1 H, d, J = 8.33 Hz), 7.34-7.41 (1 H, m), 7.52-7.63 (3 H, m), 7.93 (1 H, d, J = 1.97 Hz), 8.00-8.07 (1 H, m), 8.24 (1 H, dd, J = 4.82, 1.32 Hz), 8.48 (1 H, d, J = 2.41 Hz).
EXAMPLE 118 ((4-fr (4-Fluorophenyl) methyloxy) -3-r (3-pyridinylamino) carbonylphenyl] methyl) carbamate (E118) To a suspension of 2-. { [(4-fluorophenyl) methyl] oxy} -5 - [(Z) - (hydroxyimino) methyl] - / V-3-pyridinylbenzamide (can be prepared by Example 83; 215 mg, 0.57 mmol) in tetrahydrofuran (5 mL) was added 2M aqueous hydrochloric acid (1.72 mL). , 56.7 mmole) followed by zinc (371 mg, 5.67 mmole) at room temperature. After stirring at temperature environment for 30 min, the mixture was heated at 60 ° C for 30 min. Upon cooling, the mixture was treated with saturated sodium bicarbonate (excess). A small amount of the solution was set aside to generate the amine. Methyl chloroformate (0.53 ml, 6.80 mmol) was added to the remainder and the pH was adjusted with additional NaHCO 3 to pH 9-10. Then, the mixture was stirred at room temperature for 1 hour. The tetrahydrofuran was evaporated under reduced pressure, and the resulting aqueous layer was extracted with ethyl acetate (2 x 30 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified twice using MDAP to give the title compound. 12 mg.
MS (electrospray): m / z [M + H] + = 422 1 H NMR (400 Hz, METHANOL-d 4) 3.66 (3 H, s), 4.28 (2 H, s), 5.26 (2 H, s), 5.48 (2 H, s), 7.14 (2 H, t, J = 8.77 Hz), 7.27 (1 H, s), 7.33-7.39 (1 H, m), 7.45-7.51 (1 H, m), 7.53- 7.62 (2 H, m), 7.88 (1 H, d, J = 2.19 Hz), 7.99-8.06 (1 H, m), 8.24 (1 H, dd, J = 4.82, 1.32 Hz), 8.47 (1 H, d, J = 2.41 Hz).
EXAMPLE 119 2- (r (4-Fluorophenyl) methyl-oxy) -5- (4-morpholinylmethyl) - ^ - 4-pyridazinylbenzamide (E119) Morpholine (0.07 ml, 0.85 mmol) followed by acetic acid (0.03 ml, 0.57 mmol) were added to a suspension of 2-. { [(4-fluorophenyl) methyl] oxy} -5-formyl-N-4-pyridazinylbenzamide (can be prepared as described in Example 84; 200 mg, 0.57 mmol) in DCE (10 mL). The mixture was stirred at room temperature for 10 min and then sodium triacetoxyborohydride (133 mg, 0.63 mmol) was added. The mixture was heated at 50 ° C for 3 hr. The reaction mixture was diluted with dichloromethane (25 ml) and saturated sodium bicarbonate was added to this mixture until no effervescence was observed. The mixture was separated and the organic layer was evaporated under reduced pressure. The residue was purified using DAP to give the title compound 180 mg.
MS (electrospray): m / z [M + H] + = 423 1 H NMR (400 MHz, METHANOL-d 4) 2.42-2.55 (4 H, m), 3.56 (2 H, s), 3.64-3.75 (4 H, m), 5.28 (2 H, s), 7.1 1-7.21 (2 H, m), 7.30 (1 H, d, J = 8.55 Hz), 7.52-7.63 (3 H, m), 7.91 (1 H, d, J = 2.41 Hz), 8.07 (1 H, dd, J = 6.03, 2.74 Hz), 8.91 (1 H, dd, J = 2.85, 0.88 Hz), 8.97 (1 H, dd, J = 5.92, 0.88 Hz).
EXAMPLE 120 5- (Aminomethyl) -2- (I (3,4-difluorophenyl) methyloxy) -3-pyridinylbenzamide (E120A) and (4- (r (3,4-difiuorophenyl methyloxy 3-r (3- A B To a suspension of 2-. { [(3,4-difluorophenyl) methyl] oxy} -5 - [(Z) - (hydroxyimino) methyl] - / / - 3-pyridinylbenzamide (can be prepared as described in Example 85; 167 mg, 0.42 mmol) in tetrahydrofuran (5 mL) was added aqueous hydrochloric acid 2M (3.60 mL, 119 mmol) followed by zinc (275 mg, 4.20 mmol) at room temperature. After being stirred at room temperature for 30 min, the mixture was heated at 60 ° C for 30 min. In cooling the mixture was treated with saturated sodium bicarbonate (excess). 5- (Aminomethyl) -2-lf (3,4-difluorophenyl) methyloxy) - / \ / - 3-pyridinylbenzamide (E120A) An aliquot (10 ml) was extracted with ethyl acetate (4 x 15 ml).
The organic compounds were combined, dried (MgSO 4) and evaporated under reduced pressure to give a residue which was purified using MDAP to give 16 mg of 5- (aminomethyl) -2-. { [(3,4-difluorophenyl) methyl] oxy} - / \ / - 3-pyridinylbenzamide (E120A).
MS (electrospray): m / z [M + H] + = 370 H NMR (400 MHz, METHANOL-d4) 4.14 (2 H, S), 5.29 (2 H, s), 7.19-7.54 (5 H, m), 7.65 (1 H, dd, J = 8.55, 2.19 Hz), 7.98 (1 H, s), 8.1 1 (1 H, d, J = 8.1 1 Hz), 8.28 (1 H, d, J = 4.60 Hz), 8.49 (1 H, br. S), 8.64 (1 H, br s.) ((4- {[[3,4-difluorophenyl) methyl-oxo) -3-f (3-pyridinylamino) carbonyl-1-phenylmethyl) carbamate (120B) Methyl chloroformate (0.39 ml, 5.04 mmol) was added to the remainder of the cooled mixture and the pH was adjusted with additional NaHCO3 to pH 9-10. Then, the mixture was stirred at room temperature for 1 hour. The tetrahydrofuran was removed under reduced pressure in a Buchi rotoevaporator and the aqueous layer was extracted with ethyl acetate (2 x 30 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was subjected to a column using sodium chloride, eluting with 0-10% methanol / dichloromethane / ammonia.
Then, the mixture was purified by MDAP to give 41 mg of (. {4- {[[3,4-difluorophenyl) methyl] oxy} -3 - [(3-pyridinylamino) carbonyl] phenyl}. methyl) methyl carbamate (E120B) MS (electrospray): m / z [M + H] + = 428 1 H NMR (400 MHz, METHANOL-d 4) 3.65 (3 H, s), 4.28 (2 H, s), 5. 24 (2 H, s), 7.18-7.36 (3 H, m), 7.36-7.42 (1 H, m), 7.47 (2 H, dd, J = 8.77, 1.97 Hz), 7.80 (1 H, s) , 8.06-8.16 (1 H, m), 8.26 (1 H, d, J = 4.60 Hz), 8.59 (1 H, br. S.).
EXAMPLE 121 2-. { f (3,4-Difluorophenyl) methyloxy > -5- (1-hydroxyethyl) -A / -3-pyridinylbenzamide A solution of 2-. { [(3,4-difluorophenyl) methyl] oxy} -5-formyl-N-3-pyridinylbenzamide (can be prepared as described in Example 80; 100 mg, 0.27 mmol) in tetrahydrofuran (5 mL) was cooled to 0 ° C and methylmagnesium bromide (0.18 mL, 0.54 mmol) ) was added. The mixture was allowed to warm to room temperature and was stirred overnight. 3 eq. of methylmagnesium bromide and the mixture was stirred at room temperature ambient. Then, 5 ml of 1 M aqueous sulfuric acid were added. After stirring for 30 min, the mixture was extracted with ethyl acetate (3 x 10 mL). The organic compounds were combined, evaporated under reduced pressure and the residue was purified by MDAP to give the title compound. 48 mg.
MS (electrospray): m / z [M + H] + = 428 H NMR (400 MHz, METHANOL- / 4) 1.45 (3 H, d, J = 6.36 Hz), 4.86 (1 H, d, J = 6.58 Hz), 5.26 (2 H, s), 7.24 (3 H, d, J = 8.55 Hz), 7.37-7.43 (1 H, m), 7.43-7.51 (1 H, m), 7.55 (1 H, s), 7.90 (1 H, d, J = 2 19 Hz ), 8.06-8.18 (1 H, m), 8.26 (1 H, dd, J = 4.82, 1.32 Hz), 8.59 (1 H, d, J = 2.19 Hz) EXAMPLE 122 5- (2-Amino-4-pyridinyl) -2-r (phenylmethyl) oxy1-A / -3-pyridinylbenzamide (E122) To a microwave flask was added 5-bromo-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide (can be prepared as described in example 2; 200 mg, 0.52 mmol), 1,4-dioxane (2 mi), 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -2-pyridinamine (201 mg, 0.78 mmol), 1 sodium carbonate (1.04 ml, 1.04 mmol) ) and tetrakis (triphenylphosphino) palladium (0) (36.2 mg, 0.03 mmol). The bottle was sealed and heated at 100 ° C for 30 minutes under microwave conditions. The mixture was evaporated under vacuum and the residue was purified using MDAP to give the title compound. 41 mg.
MS (electrospray): m / z [M + H] + = 382 1 H NMR (400 MHz, CHLOROFORM-d) d ppm 5.32 (2 H, s) 7.23 (1 H, d, J = 4.82 Hz) 7 25-7.32 (1 H, m) 7.51-7.61 (7 H, m) 7.85 (1 H, dd, J = 8.55, 2.41 Hz) 7.99 (1 H, d, J = 2.63 Hz) 8.12-8.19 (1 H, m) 8.29 (1 H, dd, J = 4.71, 1.43 Hz) 8.64 -8.73 (3 H, m) 10.04 (1 H, s) EXAMPLE 123 2- (K4-Fluorophenyl) methyloxy) -N- (2-fluoro-3-pyridinium-5- (4-morpholinylcarbonylbenzamide (E123) To a solution of 2-. { [(4-fluorophenyl) methyl] oxy} -5- (4-morpholinylcarbonyl) methyl benzoate (can be prepared as described in the description 109, 93 mg, 0.25 mmol) in tetrahydrofuran (4 mL) was added lithium hydroxide (19 mg, 0.79 mmol) and water ( 1 mi). The mixture was stirred at 50 ° C for one hour, cooled and 2M hydrochloric acid (0.40 ml, 0.80 mmol) was added and the solvent was removed under vacuum. The residue was redissolved in N, N-dimethylformamide (4 ml) and diisopropylethylamine (0.1 ml, 0.62 mmol), 2-fluoro-3-pyridinamine (36.3 mg, 0.32 mmol) and HATU (284 mg, 0.75 mmol) were added. . The solvent was removed under vacuum and the residue was purified by MDAP to give the title compound as an off-white solid. 5 mg.
MS (electrospray): m / z, [M + H] + = 454 H NMR (400 MHz, DMSO-d6); 3.41-3.71 (8 H, m), 5.35 (2 H, s), 7. 23 (3 H, t, J = 8.91 Hz), 7.33-7.45 (2 H, m), 7.52-7.72 (3 H, m), 7.86-7.98 (2 H, m), 8.61 (1 H, br. s.), 10.19 (1 H, s).
EXAMPLE 124 2-. { r (4-Fluorophenyl) methyloxy) -N- (3-methyl-4-isoxazolyl) -5- (4-morpholinylcarbonylbenzamide (E124) 3-Methyl-4-isoxazolamine hydrochloride (44.9 mg, 0.33 mmol), 1 - . 1-Hydroxy-7-azabenzotriazole (41.7 mg, 0.31 mmol), diopropylethylamine (0.10 ml, 0.56 mmol) and EDC (80 mg, 0.42 mmol) were added to a solution of 2- acid. { [(4-fluorophenyl) methyl] oxy} -5- (4-morpholinylcarbonyl) benzoic acid (100 mg, 0.28 mmol) in N, N-dimethylformamide (5 mL). The solution was stirred for 18 hours before the solvent was removed under vacuum. The residue was purified by column chromatography (silica gel; 10% 7M NH3 in methanol / dichloromethane). Trituration with methanol gave the title compound as a white solid. 21 mg.
MS (electrospray): m / z, [M + H] + = 440 1 H NMR (400 MHz, DMSO- / 6); 3.61 (8 H, br. S.), 5.28 (3 H, s), 5. 75 (2 H, s), 7.25 (2 H, t, J = 8.78 Hz), 7.38 (1 H, d, J = 8.78 Hz), 7.52-7.66 (3 H, m), 7.79 (1 H, d , J = 2.26 Hz), 9.15 (1 H, s), 9.86 (1 H, s).
EXAMPLE 125 2- (r (2,4-Difluorophenyl) methoxy) -N- (2-fluoro-3-pyridinyl) -5- (4-morpholinylcarbonylbenzamide (E125) To a solution of 2-. { [(2,4-difluorophenyl) methyl] oxy]} -5- (4-morpholinylcarbonyl) methyl benzoate (can be prepared as described in the description 1 10.00 mg, 0.26 mmol) in tetrahydrofuran (THF) (4 mL) was added lithium hydroxide (26 mg, 1.09 mmol) ) and water (1 ml). The mixture was heated at 50 ° C for one hour, cooled and 2M hydrochloric acid (0.54 ml, 1.09 mmol) was added. The solvent was removed under vacuum and the residue redissolved in N, N-dimethylformamide (4 mL). Diisopropylethylamine (0.09 ml, 0.51 mmol), 2-fluoro-3-pyridineamine (34.4 mg, 0.31 mmol) and HATU (243 mg, 0.64 mmol) were added and the mixture was stirred overnight. The solvent was removed under vacuum and the residue was purified by column chromatography (silicon, 10% methanol / dichloromethane) to give an oil. Purification by MDAP gave the title compound as an off-white solid. 22 mg.
E (electroaspersion): m / z, [M + H] = 472 H NMR (400 MHz, DMSO-d6); 3.61 (8 H, br. S.), 5.40 (2 H, s), 7.15 (1 H, td, J = 8.60, 2.13 Hz), 7.29-7.43 (2 H, m), 7.49 (1 H, d , J = 8.53 Hz), 7.63-7.81 (2 H, m), 7.83-8.03 (2 H, m), 8.56-8.71 (1 H, m), 10.1 1 (1 H, s).
EXAMPLE 126 2 - ([(2,4-Difluorophenyl) methyloxy-N- (3-methyl-4-isoxazolyl) -5- (4-morpholinylcarbonylbenzamide (D126) To a solution of acid 2-. { [(2,4-difluorophenyl) methyl] oxy} -5- (4-morpholinylcarbonyl) benzoate methyl (can be prepared as described in the description 1 10; 100 mg, 0.26 mmol) in tetrahydrofuran (4 mL) was added lithium hydroxide (26 mg, 109 mmol) and water (1 mi) The mixture was heated at 50 ° C for one hour, cooled and 2M hydrochloric acid (0.54 ml, 1.09 mmol) was added. The solvent was removed under vacuum and the residue redissolved in N, N-dimethylformamide (5 ml). 3-Ethyl-4-isoxazolamine hydrochloride (42.8 mg, 0.32 mmol), 1-hydroxy-7-azabenzotriazole (39.7 mg, 0.29 mmol), diisopropylethylamine (0.09 ml, 0.53 mmol) and EDC (76 mg, 0.40 mmol) they added. The solution was stirred for 18 hours. Water (3 mL) and a pale brown solid were added which was precipitated, filtered. Recrystallization with 1: 1 methanol / DMSO gave the title compound as a white solid. 9.5 mg.
MS (electrospray): m / z, [M + H] + = 458 1 H NMR (400 MHz, DMSO-d 6); 1.86-1.99 (3 H, s), 3.41-3.66 (8 H, m), 5.29 (2 H, s), 7.12 (1 H, td, J = 8.47, 1.88 Hz), 7.22-7.34 (1H, m ), 7.40 (1 H, d, J = 8.53 Hz), 7.53-7.79 (3 H, m), 9.10 (1 H, s), 9.78 (1 H, s).
EXAMPLE 127 2- (r (4-Fluorophenyl) methyloxy) -5- (4-morpholinylcarbonyl) - / V-3-pyridinylbenzamide (E127) To a solution of 4- acid. { [(4-fluorophenyl) methyl] oxy} -3 - [(3-pyridinylamino) carbonyl] benzoic acid (can be prepared as described in the description 11 1; 62 mg, 0.17 mmole) in?,? - dimethylformamide (DMF) (5 ml) morpholine (0.03) mi, 0.34 mmole), EDC (38.9 mg, 0.20 mmol), HOBT (41.5 mg, 0.27 mmol) and N-ethylmorpholine (0.04 ml, 0.34 mmol). The mixture was stirred at room temperature overnight. The mixture was evaporated and the residue was purified by MDAP.
MS (electrospray): m / z [M + H] + = 436 1 H NMR (400 MHz, METHANOL-d 4) d ppm 3.70 (8 H, br. S.) 5.31 (2 H, s) 7.09-7.21 (2 H, m) 7.32-7.42 (2 H, m) 7.58 (2 H, dd, J = 8.66, 5.37 Hz) 7.65 (1 H, dd, J = 8.66, 2.30 Hz) 8.00 (1 H, d, J = 2.19 Hz) 8.02-8.09 (1 H, m) 8.25 (1 H, d, J = 4.17 Hz) 8.51 (1 H, d, J = 1.53 Hz).
EXAMPLE 128 2-U (4-Fluorophenyl) methynoxy) -5- (1-r2 ^ pyridinylbenzamide (E128) 3-Pyridinamine (26.5 mg, 0.28 mmol), 1-hydroxy-7-azabenzotriazole (30.7 mg, 0.23 mmol), EDC (43.3 mg, 0.23 mmol) and diisopropylethylamine (0.07 mL, 0.38 mmol) were added to a solution of acid 2-. { [(4-fluorophenyl) methyl) oxy} -5-. { 1- [2- (4-morpholinyl) ethyl] -1 H -pyrazol-4-yl} benzoic acid (can be prepared as described in the description 114; 80 mg, 0.19 mmol) in?,? - dimethylformamide (2 ml), and the reaction was stirred at room temperature overnight. The DMF was removed in a Buchi rotoevaporator. The residue was taken up in ethyl acetate (50 ml), washed with water (1 x 25 ml). The ethyl acetate layer was evaporated on a Buchi rotoevaporator under reduced pressure and the residue was purified using MDAP to give the title compound. 45 mg.
MS (electrospray): m / z [M + H] + = 502 H R N (400 MHz, METHANOL-d4) d ppm 2.41-2.54 (4 H, m) 2. 82 (2 H, t, J = 6.53 Hz) 3.59-3.71 (4 H, m) 4.28 (2 H, t, J = 6.53 Hz) 5.23 (2 H, s) 7.07-7.18 (2 H, m) 7.25 (1 H, d, J = 8.78 Hz) 7.34 (1 H, dd, J = 8.28, 4.77 Hz) 7.56 (2 H, dd, J = 8.53, 5.52 Hz) 7.68 (1 H, dd, .7 = 8.53 , 2.26 Hz) 7.80 (1 H, s) 7.91 -8.04 (2 H, m) 8.01-8.13 (1 H, m) 8.22 (1 H, dd, J = 4.89, 1.38 Hz) 8.40-8.55 (1 H, m).
EXAMPLE 129 2- (r (4-Fluorophenyl) methoxy) -N- (3-methyl-4-isoxazolyl) -5- (1-r 2 - (4-morpholinyl) ethyl-1 H -pyrazol-4-yl) benzamide (E129) 3-Methyl-4-isoxazolamine (38.0 mg, 0.28 mmol), 1-hydroxy-7- azabenzotriazole (30.7 mg, 0.23 mmole), EDC (43.3 mg, 0.23 mmole) and diisopropylethylamine (0.10 ml, 0.56 mmole) were added to a solution of 2- acid. { [(4-fluorophenyl) methyl] oxy} -5-. { 1- [2- (4-morpholinyl) ethyl] -1 H -pyrazol-4-yl} benzoic acid (can be prepared as described in the description 114; 80 mg, 0.19 mmoles) in N, N-dimethylformamide (2 ml) and the reaction mixture was stirred at room temperature overnight. The DMF was removed in a Buchi rotoevaporator. The residue was taken up in ethyl acetate (50 ml) and washed with water (1 x 25 ml). The ethyl acetate layer was evaporated on a Buchi rotoevaporator under reduced pressure and the residue was purified using MDAP. The solid obtained, after concentrating the appropriate sample, was taken up in ethyl acetate (50 ml) and washed with saturated bicarbonate (10 ml). The organic phase was dried (MgSO4) and evaporated to give the title compound as a white solid. 15 mg.
MS (electrospray): m / z [M + H] + = 506 1 H NMR (400 MHz, CHLOROFORM-d) d ppm 1.57 (3 H, s) 2.47- 2.60 (4 H, m) 2.87 (2 H, t, J = 6.65 Hz) 3.66-3.79 (4 H, m) 4.29 (2 H, t, J = 6.65 Hz) 5.20 (2 H, s) 7.13-7.23 (3 H, m) 7.54 (2 H, dd, J = 8.53, 5.27 Hz) 7.66 (1 H, dd, J = 8.53, 2.26 Hz) 7.79 (2 H, d, J = 13.80 Hz) 8.42 (1 H, d, J = 2.26 Hz) 9.1 1 (1 H, s) EXAMPLE 130 2- (r (4-Fluorofenmmetinoxi) -5- (1-r2- (methyloxy) etin-1 H -pyrazol-4-yl) -N-3-pyridinylbenzamide (E130) 3-Pyridnamine (49.0 mg, 0.52 mmol), HATU (148 mg, 0.39 mmol) and diisopropylethylamine (0.1 ml, 0.65 mmol) were added to a solution of 2-. { [(4-fluorophenyl) methyl] oxy} -5-. { 1- [2- (methyloxy) ethyl] -1 H -pyrazol-4-yl} Methyl benzoate (can be prepared as described in 1 16, 100 mg, 0.26 mmol) in N, N-dimethylformamide (5 mL) and the mixture was stirred at room temperature overnight. The DMF was evaporated under reduced pressure in a Buchi rotoevaporator. Water (5 ml) and ethyl acetate (10 ml) were added to the residue. The organics were separated and the aqueous layer was further extracted with ethyl acetate (3x1 OmI). The organic compounds were combined and evaporated. The residue was purified using MDAP to give the title compound. 36 mg.
MS (electrospray): m / z [M + H] + = 447 H NMR (400 MHz, METHANOL-d4) d ppm 3.33 (3 H, s) 3.75 (2 H, t, J = 5.14 Hz) 4.31 (2 H, t, J = 5.27 Hz) 5.23 (2 H, s) 7.14 (2 H, t, J = 8.78 Hz) 7.25 (1 H, d, J = 8.78 Hz) 7.31-7.39 (1 H, m) 7.56 (2 H, dd, J = 8.53, 5.52 Hz) 7.64-7.70 (1 H, m) 7.80 (1 H, s) 7.95 (2 H, s) 8.08 (1 H , d, J = 2.26 Hz) 8.17-8.29 (1 H, m) 8.41-8.55 (1 H, m) EXAMPLE 131 2- (r (4-Fluorophenylmethyl) -N-3-pyridinyl-5- (trifluoromethyl) benzamide (E131) EDC (122 mg, 0.64 mmol), 3-pyridinamine (59.9 mg, 0.64 mmol), HOBT (63.4 mg, 0.41 mmol) and diisopropylethylamine (0.11 mL, 0.64 mmol) were added to a solution of 2- acid. { [(4-fluorophenyl) methyl] oxy} -5- (trifluoromethyl) benzoic acid (can be prepared as described in description 119; 100 mg, 0.32 mmol) in?,? - dimethylformamide (5 ml) and the mixture was stirred at room temperature overnight. The mixture was then heated at 70 ° C for 5 hours. The mixture was diluted with water (25 ml) and extracted with ethyl acetate (3 x 25 ml). The organic compounds were combined, evaporated under reduced pressure in a Buchi rotoevaporator and the residue was purified using MDAP to give the title compound. 85 mg.
MS (electrospray): m / z [M + H] + = 391 H NMR (400 MHz, METHANOL-c / 4) d ppm 5.34 (2 H, s) 7.15 (2 H, t, J = 8.78 Hz) 7.34-7.41 (1 H, m) 7.47 (1 H, d, J = 8.78 Hz) 7.59 (2 H, dd, J = 8.53, 5.52 Hz) 7.80-7.88 (1 H, m) 8.00-8.10 (1 H, m) 8.18 (1H, d, J = 1.76 Hz) 8.25 (1 H, d, J = 3.76 Hz) 8.50 (1 H, d, J = 2.26 Hz) EXAMPLE 132 2-. { [(4-Fluorophenyl) methyloxy) -N-4-pyridazinyl-5- (trifluoromethyl) benzamide (E132) 4-Pyridazinamine (60.5 mg, 0.64 mmol), EDC (122 mg, 0.64 mmol), HOBT (63.4 mg, 0.41 mmol) and diisopropylethylamine (0.1 mL, 0.64 mmol) were added to a solution of 2- acid. { [(4-fluorophenyl) methyl] oxy]} -5- (trifluoromethyl) benzoic acid (can be prepared as described in the description 1 19; 100 mg, 0.32 mmol) in N, N-dimethylformamide (20 ml) and the mixture was stirred at room temperature overnight. The mixture was then heated at 70 ° C overnight (NOTE: it would be better to prepare the acid chloride and react with the amine). The mixture was diluted with water (25 ml) and extracted with ethyl acetate (3 x 25 ml). The organic compounds were combined, evaporated under reduced pressure in a Buchi rotoevaporator and the residue was purified using MDAP to give the title compound, 70 mg.
MS (electrospray): m / z [M + H] + = 392 1 H NMR (400 MHz, METHANOL-c) d ppm 5.34 (2 H, s) 7.15 (2 H, t, J = 8.78 Hz) 7.48 (1 H, d, J = 8.78 Hz) 7.57 (2 H, dd, J = 8.53, 5.52 Hz) 7.80-7.93 (1 H, m) 8.08 (1 H, dd, J = 5.90, 2.64 Hz) 8.15 (1 H, d, J = 2.01 Hz) 8.92- 9.05 (2 H, m ) EXAMPLE 133 2- (r (4-Fluorophenyl) methoxy) -N- (3-methyl-4-isoxa2oliH-5- (trifluoromethyl) benzamide (E133) To a solution of acid 2-. { [(4-fluorophenyl) methyl] oxy} -5- (trifluoromethyl) benzoic acid (can be prepared as described in the description 1 19; 100 mg, 0.32 mmol in?,? - dimethylformamide (4 mL) was added EDC (122 mg, 0.64 mmol), HOBT (63.4 mg. 0.41 mmol), 3-methyl-4- Soxazolamine (86 mg, 0.64 mmol), DIPEA (0.22 mL, 1.27 mmol) and the mixture was stirred at room temperature overnight. The mixture was then heated at 70 ° C overnight (NOTE: it would be better to prepare the acid chloride and react it with the amine). The mixture was diluted with water (25 ml) and extracted with ethyl acetate (3 x 25 ml). The organics were combined, evaporated under reduced pressure in a Buchi rotoevaporator and the residue was purified using MDAP to give the title compound. 33 mg.
MS (electrospray): m / z [M + H] + = 395 H NMR (400 MHz, METHANOL-d4) d ppm 1.72 (3 H, s) 5.34 (2 H, s) 7.19 (2 H, s) 7.48-7.56 (1 H, m) 7.57-7.67 (2 H, m) ) 7.83-7.91 (1 H, m) 8.24-8.34 (1 H, m) 9.05 (1 H, s) EXAMPLE 134 2- (f (4-Fluorophenyl) methyloxy) - / V-4-isoxazolyl-5- (1-methyl-1H-pyrazole-4- iDbenzamide (E134) A mixture of acid 2-. { [(4-fluorophenyl) methyl] oxy} -5- (1-methyl-1H-pyrazol-4-yl) benzoic acid (can be prepared as described in description 121; 100 mg, 0.31 mmol), isoxazol-4-amine (38.6 mg, 0.46 mmol), HOBT (70.4 mg, 0.46 mmol) and EDC (88 mg, 0.46 mmol) in?,? - dimethylformamide (5 mL) was stirred at room temperature for 16 hours. Water (50 ml) was added. The mixture was extracted with ethyl acetate (50 ml x 3). The combined organic layers were washed with brine (50 mL), dried over a2SO4 and concentrated to give the crude product. The crude product was purified by CLAR-prep (instrument: Gilson GX-281; Column: Shimadzu PRC-ODS, 15.0 um, 19 mm * 250 mm; Mobile phase: A: 0.05% NH3H20 / H20; B: CH3CN; Gradient 0 -8min 42-54% B; 8-12min 95%; flow rate (ml / min) 30.00; Detection wavelength (nm) 214; Retention time (min) 7.5) to give the title compound as a solid white. 17 mg. 1 H NMR (400 MHz, DMSO-d 6): 3.85 (3H, s), 5.25 (2H, s), 7.20-7.26 (3H, m), 7.53-7.55 (2H, q), 7.67-7.70 (1H, dd, J- 2.4 Hz, J = 8.8 Hz), 7.79 (1H, d, J = 2.4 Hz), 7.85 (1 H, s), 8.13 (1 H, s), 8.63 (1 H, s), 9.24 (1H, s), 10.49 (1 H, s) EM (electrospray): m / z [M + H] + = 393.1 EXAMPLE 135 2- (f (4-Fluorophenyl) methyanoxy) - / V- (5-methyl-4-isoxazolyl) -5- (1-methyl-1H-pyrazol-4-yl) benzamide (E135) A mixture of acid 2-. { [(4-fluorophenyl) methyl] oxy} -5- (1-methyl-1H-pyrazol-4-yl) benzoic acid (can be prepared as described in description 121; 80 mg, 0.25 mmol), 3-methylisoxazol-4-amine (49.5 mg, 0.37 mmol) ), HOBT (56.3 mg, 0.37 mmol) and EDC (70.5 mg, 0.37 mmol) in N, N-dimethylformamide (2 mL) was stirred at room temperature for 16 hours. Water (50 ml) was added. A white precipitate was filtered, washed with ethyl acetate and dried under vacuum to give the title compound as a white solid. 54 mg. 1 H NMR (400 MHz, DMSO-d 6): 1.99 (3 H, s), 3.86 (3 H, s), 5.25 (2 H, s), 7.25 (2 H, t, J = 8.8 Hz), 7.32 (2 H, d, J = 8.4 HZ), 7.59-7.62 (1 H, q, J = 2.8, J = 8.8), 7.73-7.75 (1 H, dd, J = 2.4 Hz, J = 8.4 Hz), 7.88 (1 H , s), 7.92 (1 H, d, J = 2.4), 8.16 (1 H, s), 9.17 (1 H, s), 9.88 (1 H, s) EM (electrospray): m / z [+ H] + = 407.1 EXAMPLE 136 2- (r (4-Fluorophenyl) methyloxy> -5-r3- (4-morpholinyl) propin-N-3-pyridinylbenzamide (E136) To a solution of 2-. { [(4-fluorophenyl) methyl] oxy} Methyl (3- (4-morpholinyl) propyl] benzoate (can be prepared as described in the description 124; 166 mg, 0.43 mmol) in tetrahydrofuran (6 ml) was added lithium hydroxide (61.6 mg, 2.57 g. mmoles) and water (1.5 mi). The mixture was stirred at 50 ° C for 3 hours, cooled and acidified with 2M hydrochloric acid (1.29 ml, 2.57 mmol). The solvent was removed under vacuum to give a residue. The residue was redissolved in N, N-dimethylformamide (3 ml) and diisopropylethylamine (0.15 ml, 0.86 mmol), 3-aminopyridine (52.4 mg, 0.56 mmol), 1-hydroxy-7-azabenzotriazole (70.0 mg, 0.51 mmol). and EDC (140 mg, 0.73 mmol). The solution was stirred overnight, the solvent was removed under vacuum and the residue was purified by MDAP to give the title compound as a white solid. 25 mg.
MS (electrospray): m / z [M + H] + 450 H NMR (DMSO-d6): 1.72 (2 H, quin, J = 7.47 Hz), 2.19-2.40 (6 H, m), 2.60 (2 H, t, J = 7.53 Hz), 3.57 (4 H, t , J = 4.52 Hz), 5.20 (2 H, s), 7.09-7.27 (3 H, m), 7.31-7.42 (2 H, m), 7.49-7.64 (3 H, m), 7.97-8.12 (1 H, m), 8.27 (1 H, dd, J = 4.64, 1, 38 Hz), 8.66 (1 H, d J = 2.26 Hz), 10.29 (1 H, s).
EXAMPLE 137 2- (r (4-Fluorophenyl) methyloxy) -5- (1-r2- (4-morpholinyl) etin-1H-pyrazol-4-yl> -N-4-pyridazinylbenzamide (E137) To a solution of acid 2-. { [(4-fluorophenyl) methyl] oxy} -5-. { 1- [2- (4-morpholinyl) ethyl] -1 H -pyrazol-4-yl} benzoic acid (can be prepared as described in the description 1 14; 220 mg, 0.52 mmol) in N, N-dimethylformamide (10 ml) was added diisopropylethylamine (0.18 ml, 1.03 mmol), 1-hydroxy-7-azabenzotriazole (84 g. mg, 0.62 mmole), 4-pyridazinamine (59.0 mg, 0.62 mmole) and EDC (149 mg, 0.78 mmole). The solution was stirred for 3 hours, then?,? - dimethylformamide was removed under vacuum and redissolved in ethyl acetate (10 ml). The solution was washed with water (3 x 10 mL), dried (MgSO4) and the solvent was removed under vacuum. Trituration with 1: 1 methanol / dimethyl sulfoxide gave the product as a brown solid (12 mg, 5% yield). The filtrate was purified by MDAP to give a brown solid which was partitioned between NaHCO3 solution (5 ml) and ethyl acetate (10 ml). The organic layer was dried (MgSO4) and the solvent was removed under vacuum to give an oil which was lyophilized to give a white solid. This was combined with the previous culture to give the title compound as a white solid. 27 mg.
MS (electrospray): m / z [M + H] + 503 1 H NMR (DMSO-d 6): 2.33-2.44 (4 H, m), 2.73 (2 H, t, J = 6.65 Hz), 3.49-3.63 (4 H, m), 4.23 (2 H, t, J = 6.53 Hz), 5.23 (2 H, s), 7.12-7.26 (2 H, m), 7.30 (1 H, d, .7 = 8.78 Hz), 7.55 (2 H, dd, J = 8.41, 5.65 Hz), 7.74 (1 H, dd, J = 8.66, 2.38 Hz), 7.81 (1 H, d, J = 2.26 Hz), 7.88 (1 H, s), 8.02 (1 H, dd, J = 5.77, 2.76 Hz), 8.21 (1 H, s), 9.06 (1 H, d, J = 5.77 Hz), 9.27 (1 H, d, J = 2.01 Hz), 10.80 (1 H, s).
Biological data Production of 6His-Tev-LRRK2 (1326-2527) An LRRK2 cDNA encoding residues 1326-2527 was obtained from Dundee University (described in M. Jaleel et al., 2007, Biochem J, 405: 407-417). This gene fragment was subcloned into pFB-HTb (Invitrogen) using BamHI and NotI restriction sites. Plasmid LRRK2 was recombined in the baculovirus genome according to the BAC-a-BAC protocol described by Invitrogen. Transfection in insect cells of Spodoptera frugiperda (Sf9) was performed using Cellfectin (Invitrogen), in accordance with the manufacturer's protocol.
The Sf9 cells were grown in Excell 420 growth medium (SAFC Biosciences) at 27 ° C, 80 rpm in a shake flask to a sufficient volume to inoculate a bioreactor. The cells were grown in a 100 liter working volume bio-processor (Applikon) at 27 ° C, 40% dissolved oxygen and a stirring rate of 60-150 rpm until the required volume was achieved with a cell concentration of approximately 4xe6 cells / ml. The insect cells were infected with Baculovirus at a multiplicity of infection (MOI) of 3. The culture was continued during an expression phase of 48 hours. The infected cells were removed from the growth medium by centrifugation at 2500 g using a Viafuge (Carr) continuous centrifuge at a flow rate of 80 liters / hour. The cell pellet was immediately frozen and subsequently supplied for purification.
A 100 g pellet was allowed to thaw in a 27 ° C water bath with 200 μl pH regulator / pH regulator A (50 mM Tris-HCI pH8.5, 300 mM NaCl, 1 mM DTT , 10% glycerol, 1 ml / L full protease inhibitor cocktail Calbiochem and benzonase (20 ul / 300 ml) before being homogenized in a dounce homogenizer on ice using 20 strokes per 100 ml. The suspension was then centrifuged at 100,000 g for 90 min at 4 ° C.
The lysate was decanted from the insoluble pellet and loaded (at 1.5 ml / min in a volume of one cycle) into a 5 ml hisHP column which had been pre-equilibrated with 10 column volumes of pH regulator A. column was then washed with 10 column volumes of pH A regulator, 10 column volumes of pH regulator B (pH regulator A + 1 NaCl) and 10 volumes of buffer column of pH B (pH regulator A + 20). mM of imidazole). The column was then eluted with 15 column volumes of pH D regulator (pH regulator A + 300mm imidazole) collecting fractions of 2.5 ml. All washes and elution were conducted at 2.5 ml / min.
Fractions identified by SDS-PAGE as containing protein of interest were placed in stock and loaded directly onto a Superdex 200 pg column of 320 ml which was pre-equilibrated with pH regulator E (50 mM Tris-HCl pH8. 5, 300 mM NaCl, 10% glycerol, 1 mM DTT). The column was loaded and eluted with 1.2 column volumes of pH regulator E at 3 ml / min collecting fractions of 2 ml.
Fractions identified by SDS-PAGE as containing protein of interest were tested for activity.
Production of Biotin-LRRKtide The peptide (biotin-RLGRDKYKTLRQIRQGNTKQR-OH) was assembled at a 0.2 mM scale using FMOC solid phase peptide synthesis on an ACT 357 MPS automated peptide synthesizer. The resulting crude peptide was digested from the resin using a mixture of 95: 2.5: 2.5 trifluoroacetic acid: triisopropyl) silane: water. The digested crude peptide was purified by reverse phase HPLC, eluting with a 5-35% gradient of 0.1% trifluoroacetic acid / acetonitrile in 0.1% trifluoroacetic acid / water.
Production of GST-PS-Moesin (400-577) A fragment of human moesin (400-577) was amplified by PCR using a full-length cDNA clone encoding human moesin (described in M. Jaleel et al., 2007, Biochem J, 405: 407-417) as a template . The fragment was subcloned in pGEX6P1 (Amersham) using restriction sites BamHI and Xhol. The moesin plasmid was transformed into BL21 * (DE3) competent cells (Invitrogen) for expression.
Transformed cells were cultured in LB medium (10 g / L tryptone, 5 g / L yeast extract, 10 g / L NaCl) at 37 ° C. Once the culture had reached an optical density (600 nm) of 0.5, it was induced with 0.1 mM IPTG and cultured at 30 ° C for 20 hr. The cells were then harvested by centrifugation at 4,400 rpm for 20 min at 4 ° C and the cell pellets were stored at -80 ° C. 70 g of cell pellet was thawed at room temperature in 280 ml of pre-cooled lysis pH buffer (50 mM Tris-HCl pH 7.5, 1% Triton X-100, 0.27 M Sucrose, 5 mM beta -mercaptoethanol, 1 ml / L of Calbiochem complete protease inhibitor cocktail, 500 mM NaCl, 1 mM sodium orthovanadate, 10 mM 2- sodium glycerophosphate, 50 mM NaF, 5 mM sodium pyrophosphate, 0.1 mg / L lysozyme, 0.1 ml / L) for 30 minutes with constant agitation. The suspension was then sonicated in a beaker in an ice-water bath at 40% amplitude for 5 minutes, using a pulse of 9.9 sec at 9.9 sec off. After sonication, the lysate was clarified by centrifugation at 100,000 g for 60 min.
Four 5 ml GST-HP columns were connected in series and pre-equilibrated with 10 column volumes of pH regulator F (50 mM Tris / HCl pH 7.5, 0.27 M sucrose, 5 mM beta-mercaptoethanol, 1 ml / L of Calbiochem complete protease inhibitor, 500 mM NaCl). The clarified lysate was loaded onto the column at 1 ml / min. The non-absorbed fraction was retained. The column was then washed with 10 column volumes of pH buffer at 3 ml / min (the non-absorbed fraction was retained). The column was then eluted at 2 ml / min using pH regulator G (pH regulator F plus 20 mM reduced glutathione) collecting fractions of 10 ml. The fractions containing protein of interest were identified using SDS-PAGE and put in stock.
A Superdex 200 pg column of 500 ml was pre-equilibrated in pH regulator H (50 mM Tris-HCl pH 6.4, 0.27 M sucrose, 5 mM Beta-mercaptoethanol, 50 mM NaCl). Fractions in stock were loaded onto the column at 2 ml / min. The column was then eluted in 1.2 column volumes of pH regulator H at 2 ml / min, collecting fractions of 2 ml. The fractions containing protein of interest were identified by SDS-PAGE and put in stock and tested for activity.
The compounds of the formula (I) can be tested for in vitro kinase activity in accordance with the following tests, using the unnatural, in vitro, moesin and the longer Biotin-LRRKtide substrates. Moesin and a shorter version of the peptide were identified as substrates in Jaleel ef al, (2007, Biochem J, 405: 307-317).
Peptide substrate test LRRK2 a) 100 or a serial dilution of 1: 4 of test compound with a final test concentration higher than 30 μ? it is added to certain wells in a black plate of 384 wells of low volume. 100 or DMSO are used in certain wells as controls. b) 3 pl of enzyme solution (80 nM of purified recombinant 6His-Tev-LRRK2 (1326-2527) in a test pH buffer 50 mM Hepes (pH 7.2), 10 mM MgCl2, 150 mM NaCl, 5% glycerol, 0.0025% Triton X-100 and 1 mM DTT) is added to certain wells. 3 μ? pH regulator test is added to certain wells as a control of 100% inhibition (if enzyme). c) After incubation at room temperature for 30 minutes, 3 pl of substrate solution (2 μ? of Biotin-LRRKtide peptide substrate and ATP to Km in test pH buffer) is added to each well. The plates are then incubated for an additional 1-2 hours at room temperature (the incubation time varies depending on the speed and linearity of reaction with different batches of enzyme). d) 6 μ? of detection solution (50 nM streptavidin SureLight® APC (PerkinElmer), 4 nM anti-rabbit IgG antibody labeled with Eu-W1024 (PerkinElmer), 1: 500 dilution (dilution determined on a batch to batch basis) of Phospho-Ezrin (Thr567) / Radixin (Thr564) / Moesin (Thr558) monoclonal antibody (New England Biolabs) and 60 mM EDTA in a pH regulator : 40 mM Hepes (pH 7.2), 150 mM NaCl, 0.03% BSA) is added to each well. The plates were then incubated for an additional 2 hours at room temperature before being read in a suitable plate reader (Excitation 330 nm, emission 620 nm (Eu) and 665 nm (APC)). The data is analyzed using the ActivityBase software (IDBS).
LRRK2 AlphaScreen protein substrate test a) 100 or a serial dilution of 1: 4 test compound with a final test concentration higher than 30 μ? it is added to certain wells in a black plate of 384 wells of low volume. 100 or DMSO are used in certain wells as controls. b) 3 μ? of enzyme solution (80 nM of purified recombinant 6His-Tev-LRRK2 (1326-2527) in a test pH buffer: 50 mM Hepes (pH 7.2), 10 mM MgC, 150 mM NaCl, 5% glycerol , 0.0025% Triton X-100 and 1 mM DTT) is added to certain wells. 3 μ? pH regulator test is added to certain wells as a control of 100% inhibition (if enzyme). c) After incubation at room temperature for 30 minutes, 3 μ? of substrate solution (200 nM of GST-PS-Moesin (400-577) and ATP to Km in test pH buffer) is added to each well. The plates are then incubated for an additional 1-2 hours at room temperature (the incubation time varies depending on the speed and linearity of reaction with different batches of enzyme). d) 6 μ? of detection solution (1: 250 dilution of AlphaLisa protein A acceptor accounts (PerkinElmer), 1: 64 dilution of AlphaLisa glutamate donor beads (PerkinElmer) and 1: 600 dilution (dilution determined on a batch basis batch) of Phospho-Ezrin (Thr567) / Radixin (Thr564) / Moesin (Thr558) monoclonal antibody (New England Biolabs) in a pH buffer: 50 mM Hepes (pH 7.5), 250 mM NaCl, 60 mM EDTA , 1% PEG and 0.01% Brij 35) is added to each well. The plates were then incubated for an additional 2 hours at room temperature in the dark before being read in an EnVision ™ plate reader with HTS turbo AlphaScreen option module and AlphaScreen values. The data is analyzed using the ActivityBase software (IDBS).
Desensitized protein substrate test LRRK2 AlphaScreen This was conducted as described for the LRRK2 alphascreen protein substrate test, with the following differences: 1. The concentration of ATP in the substrate solution was 2 mM. 2. The plates were incubated for 20 minutes at room temperature after the addition of the substrate solution.
Pharmacological data The compounds of examples 1-28, 28A, 28B, 29-51, 53, 57-61, 63, 65, 69-71, 73-76, 86-119, 122-130 and 132-137 were tested in the Peptide substrate test LRRK2 and showed a plC50 > 5.6. Very particularly, the compounds of Examples 1-6, 26, 28, 28A, 29-33, 37-38, 44-49, 51, 57-61, 63, 69-71, 73-76, 86-110, 1 12, 1 13, 1 15-119, 122, 123, 125,127-131 and 134-136 were tested in the LRRK2 peptide substrate test and showed a plC50 > 7.0 Very particularly still, the compounds of Examples 32, 44-45, 47, 49, 58-59, 61, 73-76, 86-87, 89-93, 97, 99-101, 103-104, 107, 1 16, 118, 128 and 130 were tested in the LRRK2 peptide substrate test and showed a plC50 > 8.0. The compounds of examples 1-21, 23-28 and 29-33 were tested in the LRRK2 protein substrate test alphascreen and showed a plC50 = 5.1. Most particularly, the compounds of Examples 1 -15, 26 and 28-33 were tested in the LRRK2 protein substrate test alphascreen and showed a plC50 = 7.0.
The compound of Example 22 was tested in the LRRK2 protein substrate test alphascreen and showed a plC50 <1. 4.6.
The compounds of Examples 1-6, 8-10, 2, 14, 16, 21, 23, 28, 28A, 28B, 29-33, 35-39, 44-51, 54, 58, 61, 63-65 , 69-71, 73-76, 86, 87, 89-97, 99-101, 103-19, 122, 123, 125-128, 30-32, 134 and 136 were tested in the desensitized protein substrate test LRRK2 alphascreen and showed a plC50 > 4.7 (excess of ATP present). Most particularly, the compounds of Examples 91, 93, 97, 99-101, 104, 16 and 130 were tested on the desensitized protein substrate test LRRK2 alphascreen and showed a plC50 = 7.0 (excess of ATP present).
The compounds of examples 7, 11, 3, 15, 17-20, 22, 24, 27, 34, 40-43, 52, 53, 55-57, 59-60, 62, 88, 98, 102, 120A , 120B, 124, 29 and 133 were tested in the LRRK2 alphascreen desensitized protein substrate test and showed a plC50 <1. 4.6 (excess of ATP present).
The compounds of examples 38, 69, 93, 94, 17, 123, 27, 128, 129, 130, 31 and 136 were tested in the LRRK2 peptide substrate test and in the desensitized protein substrate assay LRRK2 alphascreen. The values of the average of plC50 for each compound are indicated in the attached table:

Claims (14)

    NOVELTY OF THE INVENTION
  1. CLAIMS composed of the formula (I) or a salt thereof wherein: A represents pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-5-yl, 1,3-oxazol-2-yl, 1 H-pyrazole- 4-ylo or isoxazol-4-yl or a group of the formula (a) wherein * represents the point of attachment: wherein when A represents pyridin-3-yl, the pyridinyl ring may be optionally substituted in the 2-position by fluoro, methoxy or CH 2 OH, in the 4-position by methyl or CH 2 OH, or in the 5-position by fluoro; when A represents 1 H-pyrazol-4-yl, the pyrazolyl ring may be optionally substituted at the 1-position by methyl, and wherein A represents isoxazol-4-yl, the isoxazolyl ring may be optionally substituted in the 3-position by methyl or in the 5-position by methyl; R1 represents halogen, halogenalkyl of d.3, hydroxy, CN, -0 (CH2) 2O (CH2) 2NH2, -CNOH, (O) n (CH2) pR10, - (CO) R10, R3, - (S02) R13, (C1-3 alkylene) (CO) qR14, (CH = CH) (CO) R14, (Ci-3 alkylene) NHCOR14, monoheterocyclic ring containing -O-nitrogen with the proviso that the atom directly attached the oxygen is not nitrogen, or a nitrogen-containing heteroaryl ring, wherein the nitrogen-containing monoheterocyclic ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing heteroaryl ring is optionally substituted by one, two or three groups selected from NH2, (alkylene of C-i_3) R13, (C1-3 alkylene) (CO) qR14, Ci-3 alkyl and halogen; n and q independently represent 0 or 1; p represents 1, 2 or 3; R 2, R 3, R 4, R 5 and R 6 independently represent hydrogen, halogen, CN, C 1-3 alkyl or C 1-3 alkoxy; R7 and R8 independently represent hydrogen or Ci-2 alkyl; R9 represents hydrogen, halogen, Ci-2 alkyl, C1.2 alkoxy, -CH2CO2H or -CONHCH3; R10 represents hydrogen, Ci-3 alkyl, -NR1 1 R12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups; R 11 and R 2 are independently selected from hydrogen and Ci. 3 alkyl, wherein said Ci-3 alkyl group is optionally substituted with one, two or three halogen, hydroxy, cyano or Ci-2 alkoxy groups; R 3 represents -NR 11 R 12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached by a nitrogen atom; and R 4 represents hydroxy or Ci-3 alkoxy; with the proviso that the compound of the formula (I) is not: 2 - [(phenylmethyl) oxy] - / V-3-pyridinyl-5- (1-pyrrolidinylsulfonyl) benzamide; 2-. { [(3,4-difluorophenyl) methyl] oxy} -5- (1-hydroxyethyl) - / V-4-pyridazinylbenzamide; 5-bromo-2- (2-chlorobenzyloxy) -N- (pyridin-3-yl)) benzamide; 5-chloro-2 - [(phenylmethyl) oxy] -N-3-pyridinylbenzamide; 5-bromo-A / -. { 3 - [(methylamino) carbonyl] phenyl} -2-[. { phenylmethyl) oxy] benzamide; or 5-chloro-2 - [(2-cyanophenyl) methoxy] -N-phenylbenzamide.
  2. 2 - . 2 - The compound of the formula (I) or a salt thereof according to claim 1, further characterized in that R represents - (0) n (CH 2) R 10 or - (CO) R 10 wherein R 10 represents hydrogen, C1.3, -NR11R12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups and wherein n represents 0 or 1 and wherein p represents 1, 2 or 3.
  3. 3. The compound of the formula (I) or a salt thereof according to claim 1 or claim 2, further characterized in that one or two of R2, R3, R4, R5 and R6 represent fluoro and the remaining groups represent hydrogen.
  4. 4 - . 4 - The compound of the formula (I) or a salt thereof according to any of claims 1 to 3, further characterized in that R2, R3, R5 and R6 each represent hydrogen and R4 represents fluoro.
  5. 5. - The compound of the formula (I) or a salt thereof according to any of claims 1 to 4, further characterized in that R7 and R8 each represent hydrogen.
  6. 6. - The compound of the formula (I) or a salt thereof according to any of claims 1 to 5, further characterized in that A represents pyridin-3-yl, wherein the pyridinyl ring may be optionally substituted at the 2-position by fluoro, pyridazin-4-yl, H-pyrazol-4-yl, wherein the pyrazolyl ring may be optionally substituted in the 1-position by methyl, or isoxazol-4-yl, wherein the isoxazolyl ring may be optionally substituted in position 3 for methyl or in position 5 for methyl.
  7. 7. - The compound of the formula (I) or a salt thereof according to claim 1, further characterized in that: A represents pyridin-3-yl, pyridazin-4-yl, 1 H-pyrazol-4-yl or isoxazole- 4-yl, wherein when A represents pyridin-3-yl, the pyridinyl ring may be optionally substituted at the 2-position by fluoro; when A represents 1 H-pyrazol-4-yl, the pyrazolyl ring may be optionally substituted at the 1-position by methyl, and where A represents isoxazol-4-yl, the isoxazolyl ring may be optionally substituted at the 3-position. by methyl or in the 5 position by methyl; R1 represents - (0) n (CH2) pR10, - (CO) R10, R13, - (S02) R13 or a nitrogen-containing heteroaryl ring said nitrogen-containing heteroaryl ring is optionally substituted by one, two or three groups selected from NH 2, (C 1 R 13 alkylene, (C 1 alkylene. 3) (CO) qR14, C1.3 alkyl and halogen; R2, R3, R4, R5, R6 independently represent hydrogen or fluoro; R7 and R8 represent hydrogen; R 10 represents hydrogen, C 1 -3 alkyl, -NR 11 R 12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups; R11 and R12 independently represent hydrogen or Ci-3 alkyl); R13 represents -NR11R12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached by a nitrogen atom; R14 represents hydroxy or Ci ^ alkoxy; and n and q independently represent 0 or 1 and p represents 1, 2 or 3; with the proviso that the compound of the formula (I) is not 2 - [(phenylmethyl) oxy] - / v'-3-pi dinyl-5- (1-pyrrolidinylsulfonyl) benzamide.
  8. 8. The compound of the formula (I) or a salt thereof according to claim 1, further characterized in that it is a compound of the examples 1 to 137 or a salt thereof.
  9. 9. - A pharmaceutical composition comprising the compound of the formula (I) as defined in any of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  10. 10. The compound of the formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of Parkinson's disease.
  11. 1. The use of a compound of the formula (I) of any of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of Parkinson's disease.
  12. 12. - A compound of the formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament wherein: A represents pyridin-2-yl, pyridin-3-yl, pyridazin-3-yl, pyridazin-4-yl, pyrimidin-5-yl, 1,3-oxazol-2-yl, 1 H-pyrazole- 4-yl or isoxazol-4-yl or a group of the formula (a) wherein * represents the point of attachment: wherein when A represents pyridin-3-yl, the pyridinyl ring may be optionally substituted in the 2-position by fluoro, methoxy or CH 2 OH, in the 4-position by methyl or CH 2 OH, or in the 5-position by fluoro; when A represents I H-pyrazol-4-yl, the pyrazolyl ring may be optionally substituted at position 1 by methyl, and where A represents isoxazol-4-yl, the isoxazolyl ring may be optionally substituted at the 3-position by methyl or at the 5-position by methyl; R1 represents halogen, halogenalkyl of Ci_3, hydroxy, CN, -0 (CH2) 20 (CH2) 2NH2, -CNOH, (0) n (CH2) pR1 °, - (CO) R10, R13, - (S02) R13, (Ci.3 alkylene) (CO) qR14, (CH = CH) (CO) R14, (Ci-3 alkylene) NHCOR14, monoheterocyclic ring containing -O-nitrogen with the proviso that the atom directly attached to oxygen is not nitrogen, or a nitrogen-containing heteroaryl ring, wherein the nitrogen-containing monoheterocyclic ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing heteroaryl ring is optionally substituted by one, two or three groups selected from NH 2, (C 1-3 alkylene) R 13, (C 1 XCO alkylene R 1, C 1-3 alkyl and halogen, n and q independently represent 0 or 1, p represents 1, 2 or 3; R 2, R 3 , R4, R5 and R6 independently represent hydrogen, halogen, CN, Ci-3 alkyl or C- | 3 alkoxy, R7 and R8 independently represent hydrogen or Ci-2 alkyl; hydrogen, halogen, Ci-2 alkyl, C1.2 alkoxy, -CH2CO2H or -CONHCH3; R10 represents hydrogen, C1.3 alkyl, -NR11R12, or a nitrogen-containing monoheterocyclic ring said ring is optionally substituted with one, two or three methyl groups; R11 and R12 are independently selected from hydrogen and Ci-3 alkyl, wherein said C1.3 alkyl group is optionally substituted with one, two or three halogen, hydroxy, cyano or d-2 alkoxy groups; R13 represents -NR11R12, or a nitrogen-containing monoheterocyclic ring, said ring is optionally substituted with one, two or three methyl groups and wherein the nitrogen-containing monoheterocyclic ring is attached by a nitrogen atom; and R 14 represents hydroxy or C 1-3 alkoxy; with the proviso that the compound of the formula (I) is not: 2 - [(phenylmethyl) oxy] -A- -3-pyridinyl-5- (1-pyrrolidinylsulfonyl) benzamide; or 2-. { [(3,4-difluorophenyl) methyl] oxy} -5- (1-hydroxyethyl) -A / -4-pyridazinylbenzamide.
  13. 13. The compound of the formula (I) according to claim 12 or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of Parkinson's disease.
  14. 14. - A pharmaceutical composition for use in the treatment or prophylaxis of Parkinson's disease comprising the compound of the formula (I) as defined in claim 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
MX2012003778A 2009-09-29 2010-09-27 Novel compounds. MX2012003778A (en)

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